Bromodomain inhibitors

ABSTRACT

The present invention provides for compounds of formula (I) 
                         
wherein Y 1 , Y 2 , R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , and A 4 , have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents for the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprised of one or more compounds of formula (I).

This patent application claims the benefit of International PatentApplication No. PCTCN2013/088844 (filed Dec. 9, 2013). The entire textof that International Patent Application is incorporated by referenceinto this application.

BACKGROUND

Bromodomains refer to conserved protein structural folds which bind toN-acetylated lysine residues that are found in some proteins. The BETfamily of bromodomain containing proteins is comprised of four members(BRD2, BRD3, BRD4 and BRDt). Each member of the BET family employs twobromodomains to recognize N-acetylated lysine residues found primarily,but not exclusively, on the amino-terminal tails of histone proteins.These interactions modulate gene expression by recruiting transcriptionfactors to specific genome locations within chromatin. For example,histone-bound BRD4 recruits the transcription factor P-TEFb topromoters, resulting in the expression of a subset of genes involved incell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967-976(2008)). BRD2 and BRD3 also function as transcriptional regulators ofgrowth promoting genes (LeRoy et al., Mol. Cell 30: 51-60 (2008)). BETfamily members were recently established as being important for themaintenance of several cancer types (Zuber et al., Nature 478: 524-528(2011); Mertz et al; Proc. Nat'l. Acad. Sci. 108: 16669-16674 (2011);Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478:529-533 (2011)). BET family members have also been implicated inmediating acute inflammatory responses through the canonical NF-KBpathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) resultingin the upregulation of genes associated with the production of cytokines(Nicodeme et al., Nature 468: 1119-1123, (2010)). Suppression ofcytokine induction by BET bromodomain inhibitors has been shown to be aneffective approach to treat inflammation-mediated kidney disease in ananimal model (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)).BRD2 function has been linked to predisposition for dyslipidemia orimproper regulation of adipogenesis, elevated inflammatory profiles andincreased susceptibility to autoimmune diseases (Denis, DiscoveryMedicine 10: 489-499 (2010)). The human immunodeficiency virus utilizesBRD4 to initiate transcription of viral RNA from stably integrated viralDNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomaininhibitors have also been shown to reactivate HIV transcription inmodels of latent T cell infection and latent monocyte infection(Banerjee, et al, J. Leukocyte Biol. doi:10.1189/jlb.0312165). BRDt hasan important role in spermatogenesis that is blocked by BET bromodomaininhibitors (Matzuk, et al., Cell 150: 673-684 (2012)). Thus, compoundsthat inhibit the binding of BET family bromodomains to their cognateacetylated lysine proteins are being pursued for the treatment ofcancer, inflammatory diseases, kidney diseases, diseases involvingmetabolism or fat accumulation, and some viral infections, as well asfor providing a method for male contraception. Accordingly, there is anongoing medical need to develop new drugs to treat these indications.

SUMMARY

In one aspect the present invention provides for compounds of formula(I) or pharmaceutically acceptable salts thereof,

wherein

-   -   R¹ is C₁-C₃ alkyl or C₁-C₃ haloalkyl;    -   R² is H;    -   R³ is —O—C₁-C₆ alkyl, —OCD₂CH₃, or —OCD₂CD₃;    -   Y¹ is N or CR⁴, wherein R⁴ is H, C₁-C₃ alkyl, or C₁-C₃        haloalkyl;    -   A² is CR⁵, and A¹, A³, and A⁴ are CR⁶; or    -   A² is CR⁵, A¹ and A³ are CR⁶, and A⁴ is N;    -   R⁵ is —N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), —N(R^(5d))C(O)—C₁-C₆        alkylenyl-R^(5b), —N(R^(5d))SO₂—C₁-C₆ alkylenyl-R^(5c),        —N(R^(5d))C(O)N(R^(5d))-G¹, —N(R^(5d))C(O)N(R^(5d))—C₁-C₆        alkylenyl-R^(5a), —N(R^(5d))SO₂N(R^(5d))—C₁-C₆ alkylenyl-R^(5a),        —C(O)N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), or —SO₂N(R^(5d))—C₁-C₆        alkylenyl-R^(5a),        -   wherein        -   R^(5a), at each occurrence, is independently G¹, —OR^(5aa),            —OC(O)R^(5dd), —SR^(5aa), —S(O)R^(5aa), —SO₂R^(5aa),            —SO₂NR^(5bb)R^(5cc), —NR^(5bb)R^(5cc), —NR^(5bb)C(O)R^(5dd),            —NR^(5bb)SO₂R^(5dd), —NR^(5bb)C(O)OR^(5dd),            —NR^(5bb)C(O)NR^(5bb)R^(5cc), —NR^(5bb)SO₂NR^(5bb)R^(5cc),            —C(O)R^(5aa), —C(O)OR^(5aa), or —C(O)NR^(5bb)R^(5cc),        -   R^(5b) is G¹, —OR^(5aa), —OC(O)R^(5dd), —SR^(5aa),            —S(O)R^(5aa), —SO₂R^(5aa), —SO₂NR^(5bb)R^(5cc),            —N(R^(5bb))(G¹), —NR^(5bb)—(C₁-C₆ alkylenyl)-G¹,            —NR^(5bb)C(O)R^(5dd), —NR^(5bb)SO₂R^(5dd), —NR^(5bb)C(O)OG¹,            —NR^(5bb)C(O)O—(C₁-C₆ alkylenyl)-G¹,            —NR^(5bb)C(O)NR^(5bb)R^(5cc), —NR^(5bb)SO₂NR^(5bb)R^(5cc),            —C(O)R^(5aa), —C(O)OR^(5aa), or —C(O)NR^(5bb)R^(5cc),        -   R^(5c) is —OR^(5aa), —OC(O)R^(5dd), —SR^(5aa), —S(O)R^(5aa),            —SO₂R^(5aa), —SO₂NR^(5bb)R^(5cc), —NR^(5bb)R^(5cc),            —NR^(5bb)C(O)R^(5dd), —NR^(5bb)SO₂R^(5dd),            —NR^(5bb)C(O)OR^(5dd), —NR^(5bb)C(O)NR^(5bb)R^(5cc),            —NR^(5bb)SO₂NR^(5bb)R^(5cc), —C(O)R^(5aa), —C(O)OG¹,            —C(O)O—(C₁-C₆ alkylenyl)-G¹, or —C(O)NR^(5bb)R^(5cc),        -   R^(5d), at each occurrence, is independently H, C₁-C₆ alkyl,            C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹,            —OR^(5aa), —OC(O)R^(5dd), —SR^(5aa), —S(O)R^(5aa),            —SO₂R^(5aa), —SO₂NR^(5bb)R^(5cc), —NR^(5bb)R^(5cc),            —NR^(5bb)C(O)R^(5dd), —NR^(5bb)SO₂R^(5dd),            —NR^(5bb)C(O)OR^(5dd), —NR^(5bb)C(O)NR^(5bb)R^(5cc),            —NR^(5bb)SO₂NR^(5bb)R^(5cc), —C(O)R^(5aa), —C(O)OR^(5aa),            —C(O)NR^(5bb)R^(5cc), —(C₁-C₆ alkylenyl)-G¹, —(C₁-C₆            alkylenyl)-OR^(5aa), —(C₁-C₆ alkylenyl)-OC(O)R^(5dd),            —(C₁-C₆ alkylenyl)-SR^(5aa), —(C₁-C₆ alkylenyl)-S(O)R^(5aa),            —(C₁-C₆ alkylenyl)-SO₂R^(5aa), —(C₁-C₆            alkylenyl)-SO₂NR^(5bb)R^(5cc), —(C₁-C₆            alkylenyl)-NR^(5bb)R^(5cc), —(C₁-C₆            alkylenyl)-NR^(5bb)C(O)R^(5dd), —(C₁-C₆            alkylenyl)-NR^(5bb)SO₂R^(5dd), —(C₁-C₆            alkylenyl)-NR^(5bb)C(O)OR^(5dd), —(C₁-C₆            alkylenyl)-NR^(5bb)C(O)NR^(5bb)R^(5cc), —(C₁-C₆            alkylenyl)-NR^(5bb)SO₂NR^(5bb)R^(5cc), —(C₁-C₆            alkylenyl)-C(O)R^(5aa), —(C₁-C₆ alkylenyl)-C(O)OR^(5aa), or            —(C₁-C₆ alkylenyl)-C(O)NR^(5bb)R^(5cc);    -   R⁶ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, or —CN;    -   R^(5aa), R^(5bb), and R^(5cc), at each occurrence, are each        independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₆ haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹;    -   R^(5dd), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆        alkylenyl)-G¹;    -   G¹, at each occurrence, is independently aryl, heteroaryl,        heterocycle, cycloalkyl, or cycloalkenyl, each of which is        optionally substituted with 1, 2, 3, 4, or 5 R^(1g)groups,    -   Y² is -L-G²; wherein        -   L is O or N(R^(x)) wherein R^(x) is H or C₁-C₆ alkyl;        -   G² is aryl, heteroaryl, heterocycle, cycloalkyl, or            cycloalkenyl, each of which is optionally substituted with            1, 2, 3, 4, or 5 R^(2g) groups,    -   R^(1g) and R^(2g), at each occurrence, are each independently        oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆        haloalkyl, —CN, NO₂, —OR^(z1), —OC(O)R^(z2),        —OC(O)NR^(z3)R^(z4), —SR^(z1), —S(O)₂R^(z1),        —S(O)₂NR^(z3)R^(z4), —C(O)R^(z1), —C(O)OR^(z1),        —C(O)NR^(z3)R^(z4), —NR^(z3)R^(z4), —N(R^(z3))C(O)R^(z2),        —N(R^(z3))S(O)₂R^(z2), —N(R^(z3))C(O)O(R^(z2)),        —N(R^(z3))C(O)NR^(z3)R^(z4), —N(R^(z3))S(O)₂NR^(z3)R^(z4), G³,        —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆        alkylenyl)-OC(O)R^(z2), —(C₁-C₆ alkylenyl)-OC(O)NR^(z3)R^(z4),        —(C₁-C₆ alkylenyl)-S(O)₂R^(z1), —(C₁-C₆        alkylenyl)-S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-C(O)R^(z1),        —(C₁-C₆ alkylenyl)-C(O)OR^(z1), —(C₁-C₆        alkylenyl)-C(O)NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-NR^(z3)R^(z4),        —(C₁-C₆ alkylenyl)-N(R^(z3))C(O)R^(z2), —(C₁-C₆        alkylenyl)-N(R^(z3))S(O)₂R^(z2), —(C₁-C₆        alkylenyl)-N(R^(z3))C(O)O(R^(z2)), —(C₁-C₆        alkylenyl)-N(R^(z3))C(O)NR^(z3)R^(z4), —(C₁-C₆        alkylenyl)-N(R^(z3))S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-CN,        or —(C₁-C₆ alkylenyl)-G³;    -   R^(z1), R^(z3), and R^(z4), at each occurrence, are each        independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₆ haloalkyl, G³, or —C₁-C₆ alkylenyl-G³;    -   R^(z2), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G³, or —C₁-C₆        alkylenyl-G³;    -   G³ is aryl, heteroaryl, heterocycle, cycloalkyl, or        cycloalkenyl, each of which is optionally substituted with 1, 2,        3, 4, or 5 R^(3g) groups,    -   R^(3g), at each occurrence, is independently oxo, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN,        NO₂, —OR^(a), —OC(O)R^(b), —OC(O)NR^(c)R^(d), —SR^(a),        —S(O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(O)R^(a), —C(O)OR^(a),        —C(O)NR^(c)R^(d), —NR^(c)R^(d), —N(R^(c))C(O)R^(b),        —N(R^(c))S(O)₂R^(b), —N(R^(c))C(O)O(R^(b)),        —N(R^(c))C(O)NR^(c)R^(d), —N(R^(c))S(O)₂NR^(c)R^(d), —(C₁-C₆        alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆        alkylenyl)-OC(O)R^(b), —(C₁-C₆ alkylenyl)-OC(O)NR^(c)R^(d),        —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆        alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a),        —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆        alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d),        —(C₁-C₆ alkylenyl)-N(R^(c))C(O)R^(b), —(C₁-C₆        alkylenyl)-N(R^(c))S(O)₂R^(b), —(C₁-C₆        alkylenyl)-N(R^(c))C(O)O(R^(b)), —(C₁-C₆        alkylenyl)-N(R^(c))C(O)NR^(c)R^(d), —(C₁-C₆        alkylenyl)-N(R^(c))S(O)₂NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-CN;    -   R^(a), R^(c), and R^(d), at each occurrence, are each        independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or        C₁-C₆ haloalkyl, and    -   R^(b), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl.

In another aspect, the present invention provides for methods fortreating or preventing disorders that are ameliorated by inhibition ofBET. Such methods comprise of administering to the subject atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, alone, or in combination witha pharmaceutically acceptable carrier.

Some of the methods are directed to treating or preventing aninflammatory disease or cancer or AIDS.

In another aspect, the present invention relates to methods of treatingcancer in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In certain embodiments, thecancer is selected from the group consisting of: acoustic neuroma, acuteleukemia, acute lymphocytic leukemia, acute myelocytic leukemia(monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,myelomonocytic and promyelocytic), acute t-cell leukemia, basal cellcarcinoma, bile duct carcinoma, bladder cancer, brain cancer, breastcancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma,chordoma, choriocarcinoma, chronic leukemia, chronic lymphocyticleukemia, chronic myelocytic (granulocytic) leukemia, chronicmyelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent. In certain embodiments, the additionaltherapeutic agent is selected from the group consisting of cytarabine,bortezomib, and 5-azacitidine.

In another aspect, the present invention relates to methods of treatinga disease or condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein said disease or condition is selected from the group consistingof: Addison's disease, acute gout, ankylosing spondylitis, asthma,atherosclerosis, Behcet's disease, bullous skin diseases, cardiacmyopathy, chronic obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema, giant cell arteritis, glomerulonephritis, heartfailure, hepatitis, hypophysitis, inflammatory bowel disease, Kawasakidisease, lupus nephritis, multiple sclerosis, myocarditis, myositis,nephritis, organ transplant rejection, osteoarthritis, pancreatitis,pericarditis, Polyarteritis nodosa, pneumonitis, primary biliarycirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis,scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus,Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener'sgranulomatosis. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent.

In another aspect, the present invention relates to methods of treatinga chronic kidney disease or condition in a subject comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said disease or condition is selected from thegroup consisting of: diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingan acute kidney injury or disease or condition in a subject comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said acute kidney injury or disease orcondition is selected from the group consisting of: ischemia-reperfusioninduced, cardiac and major surgery induced, percutaneous coronaryintervention induced, radio-contrast agent induced, sepsis induced,pneumonia induced, and drug toxicity induced. In certain embodiments,the methods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingAIDS in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In certain embodiments, themethods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingobesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease,metabolic syndrome, hepatic steatosis, type II diabetes, insulinresistance, diabetic retinopathy or diabetic neuropathy in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof,to a subject in need thereof. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

In another aspect, the present invention relates to methods ofpreventing conception by inhibiting spermatogenesis in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof,to a subject in need thereof. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

A further aspect of the invention provides the use of a compound offormula (I), alone or in combination with at least one additionaltherapeutic agent, in the manufacture of a medicament for treating orpreventing conditions and disorders disclosed herein, and with orwithout a pharmaceutically acceptable carrier.

Pharmaceutical compositions comprising a compound of formula (I), or apharmaceutically acceptable salt, alone or in combination with at leastone additional therapeutic agent, are also provided.

DETAILED DESCRIPTION

Disclosed herein are compounds of formula (I)

wherein Y¹, Y², R¹, R², R³, A¹, A², A³, and A⁴ are defined above in theSummary of the Invention and below in the Detailed Description. Further,compositions comprising such compounds and methods for treatingconditions and disorders using such compounds and compositions are alsodisclosed.

Compounds disclosed herein may contain one or more variable(s) thatoccur more than one time in any substituent or in the formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds, which can be isolated from a reactionmixture.

Definitions

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds, reference to “optionally a pharmaceuticallyacceptable carrier” refers to a single optional pharmaceuticallyacceptable carrier as well as one or more optional pharmaceuticallyacceptable carriers, and the like.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C₂-C₆ alkenyl” means analkenyl group containing 2-6 carbon atoms. Non-limiting examples ofalkenyl include buta-1,3-dienyl, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

The term “C₂-C₆ alkenylene” means a divalent group derived from astraight or branched chain hydrocarbon of 2 to 6 carbon atoms andcontains at least one carbon-carbon double bond. Representative examplesof C₂-C₆ alkenylene include, but are not limited to, —CH═CH— and—CH₂CH═CH—.

The term “alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain radical. In some instances, the number of carbon atomsin an alkyl moiety is indicated by the prefix “C_(x)-C_(y)”, wherein xis the minimum and y is the maximum number of carbon atoms in thesubstituent. Thus, for example, “C₁-C₆ alkyl” refers to an alkylsubstituent containing from 1 to 6 carbon atoms and “C₁-C₃ alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl,1-ethylpropyl, 1,2,2-trimethylpropyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkylene” or “alkylenyl” means a divalent radical derived froma straight or branched, saturated hydrocarbon chain, for example, of 1to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylenyl) or of 1to 4 carbon atoms (C₁-C₄ alkylenyl) or of 1 to 3 carbon atoms (C₁-C₃alkylenyl) or of 2 to 6 carbon atoms (C₂-C₆ alkylenyl). Examples ofalkylene and alkylenyl include, but are not limited to, —CH₂—, —CH₂CH₂—,—C(CH₃)₂)— —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “C₂-C₆ alkynyl” as used herein, means a straight or branchedchain hydrocarbon radical containing from 2 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of C₂-C₆ alkynyl include, but are not limited, to acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “C₂-C₆ alkynylene” means a divalent group derived from astraight or branched chain hydrocarbon of from 2 to 6 carbon atomscontaining at least one triple bond. Representative examples ofalkynylene include, but are not limited to, —C≡C—, —CH₂C≡C—,—CH(CH₃)CH₂C≡C—, —C≡CCH₂—, and —C≡CCH(CH₃)CH₂—.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples ofthe aryl groups include dihydroindenyl, indenyl, naphthyl,dihydronaphthalenyl, and tetrahydronaphthalenyl. The bicyclic aryls areattached to the parent molecular moiety through any carbon atomcontained within the bicyclic ring systems.

The term “cycloalkyl” as used herein, refers to a radical that is amonocyclic cyclic alkyl, a bicyclic cycloalkyl, or a spiro cycloalkyl.The monocyclic cycloalkyl is a carbocyclic ring system containing threeto eight carbon atoms, zero heteroatoms and zero double bonds. Examplesof monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is amonocyclic cycloalkyl fused to a monocyclic cycloalkyl ring. Themonocyclic and the bicyclic cycloalkyl groups may contain one or twoalkylene bridges, each consisting of one, two, three, or four carbonatoms in length, and each bridge links two non-adjacent carbon atoms ofthe ring system. Non-limiting examples of bicyclic ring systems includebicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane,tricyclo[3.3.1.0^(3,7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3,7)]decane (adamantane). A spirocycloalkyl is a monocyclic cycloalkyl wherein two substituents on thesame carbon atom of the monocyclic cycloalkyl ring together with saidcarbon atom form a second monocyclic cycloalkyl ring. The monocyclic,the bicyclic, and the spiro cycloalkyl groups are attached to the parentmolecular moiety through any substitutable atom contained within thering system.

The term “C₃-C₆ cycloalkyl” as used herein, means cyclopropyl,cyclobutyl, cyclopentyl, and cyclohexyl.

The term “cycloalkenyl” as used herein, refers to a monocyclic or abicyclic hydrocarbon ring radical. The monocyclic cycloalkenyl hasfour-, five-, six-, seven- or eight carbon atoms and zero heteroatoms.The four-membered ring systems have one double bond, the five-orsix-membered ring systems have one or two double bonds, and the seven-or eight-membered ring systems have one, two, or three double bonds.Representative examples of monocyclic cycloalkenyl groups include, butare not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. The bicyclic cycloalkenyl is amonocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or amonocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. Themonocyclic or bicyclic cycloalkenyl ring may contain one or two alkylenebridges, each consisting of one, two, or three carbon atoms, and eachlinking two non-adjacent carbon atoms of the ring system. Representativeexamples of the bicyclic cycloalkenyl groups include, but are notlimited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyls can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “C₅-C₈ cycloalkenyl” as used herein, means a cyclohexenyl,cyclohexadienyl, cyclopentenyl, cycloheptenyl, and cyclooctenyl. TheC₅-C₈ cycloalkenyls can be attached to the parent molecular moietythrough any substitutable atom contained within the ring systems.

The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. The term “C₁-C₆ haloalkyl” means a C₁-C₆ alkylgroup, as defined herein, in which one, two, three, four, five, or sixhydrogen atoms are replaced by halogen. The term “C₁-C₃ haloalkyl” meansa C₁-C₃ alkyl group, as defined herein, in which one, two, or threehydrogen atoms are replaced by halogen. Representative examples ofhaloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl,difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl,trifluorobutyl, and trifluoropropyl.

The term “heterocycle” or “heterocyclic” as used herein, means a radicalof a monocyclic heterocycle, a bicyclic heterocycle, and a spiroheterocycle. A monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered carbocyclic ring also containing at least oneheteroatom independently selected from the group consisting of O, N, andS. A three- or four-membered ring contains zero or one double bond, andone heteroatom selected from the group consisting of O, N, and S. Whentwo O atoms or one O atom and one S atom are present in a heterocyclicring, then the two O atoms or one O atom and one S atom are not bondeddirectly to each other. A five-membered ring contains zero or one doublebond and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Examples of five-membered heterocyclic ringsinclude those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Examples of 5-memberedheterocyclic groups include tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl,imidazolinyl, isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, and3-pyrrolinyl. A six-membered ring contains zero, one, or two doublebonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Examples of six-membered heterocyclic ringsinclude those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N;1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1Q and 1 N; and 1 O and 2 N. Examples of 6-membered heterocyclic groupsinclude tetrahydropyranyl, dihydropyranyl, 1,4-dioxanyl, 1,3-dioxolanyl,1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl,piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl,1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothiopyranyl,1,1-dioxo-hexahydro-l-thiopyranyl, 1,1-dioxo-1⁶-thiomorpholinyl,thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-memberedrings contains zero, one, two, or three double bonds and one, two, orthree heteroatoms selected from the group consisting of O, N, and S.Representative examples of monocyclic heterocycles include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,4-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, thiopyranyl, and trithianyl. The bicyclic heterocycleis a monocyclic heterocycle fused to a phenyl group, or a monocyclicheterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle. Representative examplesof bicyclic heterocycles include, but are not limited to, benzopyranyl,benzothiopyranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,3,4-dihydro-2H-chromen-6-yl, 2,3-dihydro-1H-indolyl,3,4-dihydroisoquinolin-2(1H)-yl,2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl, andhexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl. The monocyclic heterocycleand the bicyclic heterocycle may contain one or two alkylene bridges oran alkenylene bridge, or mixture thereof, each consisting of no morethan four carbon atoms and each linking two non adjacent atoms of thering system. Examples of such bridged heterocycle include, but are notlimited to, azabicyclo[2.2.1]heptyl (including2-azabicyclo[2.2.1]hept-2-yl), 8-azabicyclo[3.2.1]oct-8-yl,octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). A spiro heterocycle is amonocyclic heterocycle wherein two substituents on the same carbon atomof the monocyclic heterocycle ring together with said carbon atom form asecond ring system selected from a monocyclic cycloalkyl, a bicycliccycloalkyl, a monocyclic heterocycle, or a bicyclic heterocycle.Examples of spiro heterocycle include, but not limited to,6-azaspiro[2.5]oct-6-yl, 1′H,4H-spiro[1,3-benzodioxine-2,4′-piperidin]-1′-yl, 1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl, and1,4-dioxa-8-azaspiro[4.5]dec-8-yl. The monocyclic, the bicyclic, and theSpiro heterocycles can be unsubstituted or substituted. The monocyclic,the bicyclic and the Spiro heterocycles are connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the ring systems. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized (e.g.1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl,1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally bequarternized.

The term “C₄-C₆ heterocycle” as used herein, means a 4-, 5-, or6-membered monocyclic heterocyclic ring as described above. Examples ofC₄-C₆ heterocycle include azetidinyl, oxetanyl, pyrrolidinyl,tetrahydrofuranyl, and tetrahydropyranyl.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl anda bicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered ring. The five-membered ring contains two double bonds. Thefive membered ring may contain one heteroatom selected from O or S; orone, two, three, or four nitrogen atoms and optionally one oxygen or onesulfur atom. The six-membered ring contains three double bonds and one,two, three or four nitrogen atoms. Representative examples of monocyclicheteroaryl include, but are not limited to, furanyl, imidazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. Thebicyclic heteroaryl consists of a monocyclic heteroaryl fused to aphenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, ora monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or amonocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclicheteroaryl fused to a monocyclic heterocycle. Representative examples ofbicyclic heteroaryl groups include, but are not limited to,benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl,benzoxadiazolyl, phthalazinyl,2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl,6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,quinolinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroarylgroups are connected to the parent molecular moiety through anysubstitutable carbon atom or any substitutable nitrogen atom containedwithin the ring systems. The nitrogen atom in the heteroaryl rings mayoptionally be oxidized and may optionally be quarternized.

The term “C₅-C₆ heteroaryl” as used herein, means a 5- or 6-memberedmonocyclic heteroaryl ring as described above. Examples of C₅-C₆heteroaryl include furanyl, thienyl, imidazolyl, pyrazolyl,1,2,4-oxadiazolyl, 1,2,4-trazolyl, 1,3-thiazolyl, pyridinyl, andpyrazinyl.

The term “heteroatom” as used herein, means a nitrogen, oxygen, andsulfur.

The term “oxo” as used herein, means a ═O group.

If a moiety is described as “substituted”, a non-hydrogen radical is inthe place of hydrogen radical of any substitutable atom of the moiety.Thus, for example, a substituted heterocycle moiety is a heterocyclemoiety in which at least one non-hydrogen radical is in the place of ahydrogen radical on the heterocycle. It should be recognized that ifthere are more than one substitution on a moiety, each non-hydrogenradical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moietymay be either (1) not substituted or (2) substituted. If a moiety isdescribed as being optionally substituted with up to a particular numberof non-hydrogen radicals, that moiety may be either (1) not substituted;or (2) substituted by up to that particular number of non-hydrogenradicals or by up to the maximum number of substitutable positions onthe moiety, whichever is less. Thus, for example, if a moiety isdescribed as a heteroaryl optionally substituted with up to 3non-hydrogen radicals, then any heteroaryl with less than 3substitutable positions would be optionally substituted by up to only asmany non-hydrogen radicals as the heteroaryl has substitutablepositions. To illustrate, tetrazolyl (which has only one substitutableposition) would be optionally substituted with up to one non-hydrogenradical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to 2non-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease andor its attendant symptoms.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease andor its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease andor its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another therapeutic agent ortreatment in a particular subject or subject population. For example ina human or other mammal, a therapeutically effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

The term “subject” is defined herein to refer to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

Compounds

Compounds of the invention have the general formula (I) as describedabove.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

In certain embodiments of formula (I), R¹ is C₁-C₃ alkyl or C₁-C₃haloalkyl.

In certain embodiments, R¹ is C₁-C₃ alkyl.

In certain embodiments, R¹ is methyl.

In certain embodiments, R² is H.

In certain embodiments of formula (I), R³ is —O—C₁-C₆ alkyl, —OCD₂CH₃,or —OCD₂CD₃.

In certain embodiments, R³ is —O—C₁-C₆ alkyl.

In certain embodiments, R³ is —O—C₁-C₃ alkyl.

In certain embodiments, R³ is —O—CH₂CH₃.

In certain embodiments, R³ is —OCD₂CH₃ or —OCD₂CD₃.

In certain embodiments of formula (I), Y¹ is N or CR⁴, wherein R⁴ is H,C₁-C₃ alkyl, or C₁-C₃ haloalkyl.

In certain embodiments, Y¹ is N.

In certain embodiments, Y¹ is CR⁴. In some such embodiments, R⁴ is H.

In certain embodiments of formula (I), A² is CR⁵, and A¹, A³, and A⁴ areCR⁶; or A² is CR⁵, A¹ and A³ are CR⁶, and A⁴ is N.

In certain embodiments, A² is CR⁵, and A¹, A³, and A⁴ are CR⁶.

In certain embodiments, A² is CR⁵, A¹ and A³ are CR⁶, and A⁴ is N.

In certain embodiments of formula (I), R⁵ is O—C₁-C₆ alkylenyl-R⁵a,N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b),N(R^(5d))SO₂—C₁-C₆ alkylenyl-R^(5c), N(R^(5d))C(O)N(R^(5d))-G¹,N(R^(5d))C(O)N(R^(5d))—C₁-C₆ alkylenyl-R^(5a),N(R^(5d))SO₂N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), C(O)N(R^(5d))—C₁-C₆alkylenyl-R^(5a), or SO₂N(R^(5d))—C₁-C₆ alkylenyl-R^(5a).

In certain embodiments, R⁵ is N(R^(5d))—C₁-C₆ alkylenyl-R^(5a),N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b), N(R^(5d))SO₂—C₁-C₆alkylenyl-R^(5c), or N(R^(5d))C(O)N(R^(5d))-G¹.

In certain embodiments, R⁵ is N(R^(5d))—C₁-C₆ alkylenyl-R^(5a). In somesuch embodiments, R^(5d) is H or SO₂R^(5aa). In some such embodiments,R^(5d) is H. In some such embodiments, R^(5d) is SO₂R^(5aa) whereinR^(5aa) is C₁-C₆ alkyl or —(C₁-C₆ alkylenyl)-G¹. In some suchembodiments, R^(5d) is SO₂R^(5aa) wherein R^(5aa) is C₁-C₃ alkyl or—(C₁-C₃ alkylenyl)-G¹. In some such embodiments, R^(5d) is SO₂R^(5aa)wherein R^(5aa) is C₁-C₃ alkyl or —(C₁-C₃ alkylenyl)-G¹, wherein G¹ isoptionally substituted phenyl. In some such embodiments, R^(5d) isSO₂R^(5aa) wherein R^(5aa) is ethyl. In some such embodiments, R^(5d) isSO₂R^(5aa) wherein R^(5aa) is —(CH₂)-G¹ and G¹ is optionally substitutedphenyl. In some such embodiments, R^(5a) is G¹ or —C(O)OR^(5dd). In somesuch embodiments, R^(5a) is —C(O)OR^(5dd) wherein R^(5dd) is C₁-C₆alkyl. In some such embodiments, R^(5a) is G¹. In some such embodiments,R^(5a) is G¹ wherein G¹ is phenyl, naphthyl, C₃-C₆ cycloalkyl,heterocycle, or heteroaryl, each of which is optionally substituted. Inthe embodiments wherein R^(5a) is G¹, examples of G¹ include phenyl,naphthyl, cyclopropyl, cyclohexyl, bicyclo[2.2.1]heptyl, furanyl,oxazolyl, thiazolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, pyridinyl,pyrimidinyl, pyrazinyl, 3,4-dihydro-2H-chromen-6-yl,6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl, benzoxazolyl, quinolinyl,tetrahydropyranyl, and 1,4-dioxanyl; each of which is optionallysubstituted. In some such embodiments, R^(5a) is G¹ wherein G¹ isoptinally substituted phenyl or optionally substituted cyclopropyl.

In certain embodiments, R⁵ is N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b). Insome such embodiments, R^(5d) is H, C₁-C₃ alkyl, or —(C₁-C₆alkylenyl)-G¹. In some such embodiments, R^(5d) is H. In some suchembodiments, R^(5d) is —(C₁-C₃ alkylenyl)-G¹ wherein G¹ is optionallysubstituted phenyl or optionally substituted C₃-C₆ cycloalkyl. In somesuch embodiments, R^(5d) is —(CH₂)-G¹ wherein G¹ is optionallysubstituted phenyl or optionally substituted C₃-C₆ cycloalkyl. In somesuch embodiments, R^(5d) is —(CH₂)-G¹ wherein G¹ is optionallysubstituted phenyl or optionally substituted cyclopropyl. In some suchembodiments, R^(5b) is G¹, —OR^(5aa), —S(O)₂R^(5aa),—NR^(5bb)C(O)R^(5dd), —NR^(5bb)S(O)₂R^(5dd), —C(O)R^(5aa), or—C(O)NR^(5bb)R^(5cc). In some such embodiments, R^(5b) is —OR^(5aa),—S(O)₂R^(5aa), —NR^(5bb)C(O)R^(5aa), —NR^(5bb)S(O)₂R^(5dd),—C(O)R^(5aa), or —C(O)NR^(5bb)R^(5cc). In some such embodiments whereinR^(5b) is —OR^(5aa), —S(O)₂R^(5aa), —NR^(5bb)C(O)R^(5dd),—NR^(5bb)S(O)₂R^(5dd), —C(O)R^(5aa), or —C(O)NR^(5bb)R^(5cc), R^(5aa),R^(5cc), and R^(5dd) are each independently optionally substitutedphenyl or optionally substituted benzyl; R^(5bb) is H or C₁-C₃ alkyl. Insome such embodiments, R^(5b) is G¹. In some such embodiments whereinR^(5b) is G¹, G¹ is phenyl, naphthyl, C₃-C₆ cycloalkyl, heterocycle, orheteroaryl, each of which is optionally substituted. In some suchembodiments R^(5b) is G¹, wherein G¹ is phenyl, cyclopropyl, cyclohexyl,bicyclo[2.2.1]heptyl, furanyl, oxazolyl, thiazolyl, pyrazolyl,imidazolyl, 1,2,4-triazolyl, pyridinyl, pyrimidinyl, naphthyl,pyrazinyl, benzoxazolyl, quinolinyl, 3,4-dihydro-2H-chromen-6-yl,6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl, tetrahydropyranyl, and1,4-dioxanyl; each of which is optionally substituted. In some suchembodiments R^(5b) is G¹, wherein G¹ is optionally substituted phenyl oroptionally substituted C₅-C₆ heteroaryl.

In certain embodiments, R⁵ is N(R^(5d))SO₂—C₁-C₆ alkylenyl-R^(5c). Insome such embodiments, R^(5d) is H or —(C₁-C₆ alkylenyl)-G¹.

In certain embodiments, R⁵ is N(R^(5d))C(O)N(R^(5d))-G¹. In some suchembodiments, R^(5d) is H. In some such embodiments, G¹ is optionallysubstituted phenyl.

In certain embodiments of formula (I), R⁶ is H, C₁-C₆ alkyl, halogen,C₁-C₆ haloalkyl, or —CN.

In certain embodiments, R⁶ is H, C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl,or —CN.

In certain embodiments, R⁶ is H.

In certain embodiments of formula (I), Y² is -L-G²; wherein L is O orN(R^(x)), R^(x) is H or C₁-C₆ alkyl; and G² is aryl, heteroaryl,heterocycle, cycloalkyl, or cycloalkenyl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 R^(2g) groups.

In certain embodiments L is O.

In certain embodiments, L is N(R^(x)) wherein R^(x) is H or C₁-C₆ alkyl.In some such embodiments, R^(x) is H.

In certain embodiments of formula (I), G² is phenyl, C₃-C₆ cycloalkyl,or C₄-C₆ heterocycle; each of which is optionally substituted with 1, 2,3, 4, or 5 R^(2g) groups. In some such embodiments, R^(2g) is C₁-C₃alkyl, halogen, C₁-C₃ haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H,C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In some such embodiments, R^(2g) ishalogen. In some such embodiments, R^(2g) is F.

In certain embodiments of formula (I), G² is phenyl or C₃-C₆ cycloalkyl;each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(2g)groups. In some such embodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃haloalkyl. In some such embodiments, R^(2g) is halogen. In some suchembodiments, R^(2g) is F.

In certain embodiments, G² is phenyl or cyclopropyl; each of which isoptionally substituted with 1, 2, or 3 R^(2g) groups. In some suchembodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or—OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In somesuch embodiments, R^(2g) is halogen. In some such embodiments, R^(2g) isF.

In certain embodiments, G² is phenyl that is substituted with 1, 2, or 3R^(2g) groups. In some such embodiments, R^(2g) is C₁-C₃ alkyl, halogen,C₁-C₃ haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, orC₁-C₃ haloalkyl. In some such embodiments, R^(2g) is halogen. In somesuch embodiments, R^(2g) is F.

In certain embodiments, G² is cyclopropyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups. In some such embodiments,R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or —OR^(z1)wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In some suchembodiments, R^(2g) is halogen. In some such embodiments, R^(2g) is F.

Various embodiments of substituents Y¹, Y², R¹, R², R³, A¹, A², A³, andA⁴ have been discussed above. These substituents embodiments can becombined to form various embodiments of compounds of formula (I). Allembodiments of compounds of formula (I), formed by combining thesubstituent embodiments discussed above are within the scope ofApplicant's invention, and some illustrative embodiments of thecompounds of formula (I) are provided below.

In one embodiment, the invention is directed to compounds of formula(I), wherein L is O, and G² is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆heterocycle; each of which is optionally substituted with 1, 2, 3, 4, or5 R^(2g) groups. In some such embodiments, R^(2g) is C₁-C₃ alkyl,halogen, C₁-C₃ haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃alkyl, or C₁-C₃ haloalkyl. In some such embodiments, R^(2g) is halogen.In some such embodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein A² is CR⁵, A¹, A³, and A⁴ are CR⁶; and R⁵ isN(R^(5d))—C₁-C₆ alkylenyl-R^(5a), N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b),N(R^(5d))SO₂—C₁-C₆ alkylenyl-R^(5c), or N(R^(5d))C(O)N(R^(5d))-G¹. Insome such embodiments, R⁶ is H.

In one embodiment, the invention is directed to compounds of formula(I), wherein A² is CR⁵, and A¹ and A³ are CR⁶, A⁴ is N, and R⁵ isN(R^(5d))—C₁-C₆ alkylenyl-R^(5a), N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b),N(R^(5d))SO₂—C₁-C₆ alkylenyl-R^(5c), or N(R^(5d))C(O)N(R^(5d))-G¹. Insome such embodiments, R⁶ is H.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, and R³ is —O—C₁-C₃ alkyl. In somesuch embodiments, R⁴ is H.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,and A¹, A³, and A⁴ are CR⁶. In some such embodiments, R⁴ is H. In somesuch embodiments, R⁶ is H.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, and G² is phenyl or C₃-C₆ cycloalkyl;each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(2g)groups. In some such embodiments, R⁴ is H. In some such embodiments, R⁶is H. In some such embodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃haloalkyl. In some such embodiments, R^(2g) is halogen. In some suchembodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl or C₃-C₆ cycloalkyl; eachof which is optionally substituted with 1, 2, 3, 4, or 5 R^(2g) groups;and R⁵ is N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), N(R^(5d))C(O)—C₁-C₆alkylenyl-R^(5b), N(R^(5d))SO₂—C₁-C₆ alkylenyl-R^(5c), orN(R^(5d))C(O)N(R^(5d))-G¹. In some such embodiments, R⁴ is H. In somesuch embodiments, R⁶ is H. In some such embodiments, R^(2g) is C₁-C₃alkyl, halogen, C₁-C₃ haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H,C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In some such embodiments, R^(2g) ishalogen. In some such embodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))—C₁-C₆alkylenyl-R^(5a), N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b),N(R^(5d))SO₂—C₁-C₆ alkylenyl-R^(5c), or N(R^(5d))C(O)N(R^(5d))-G¹; andR⁴ is H. In some such embodiments, R⁶ is H. In some such embodiments,R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or —OR^(z1)wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In some suchembodiments, R^(2g) is halogen. In some such embodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))—C₁-C₆alkylenyl-R^(5a); and R⁴ is H. In some such embodiments, R⁶ is H. Insome such embodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl,—CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.In some such embodiments, R^(2g) is halogen. In some such embodiments,R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))—C₁-C₆alkylenyl-R5a; R^(5d) is H or SO₂R^(5aa); R^(5a) is G¹; and R⁴ is H. Insome such embodiments, R⁶ is H. In some such embodiments, R^(2g) isC₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or —OR^(z1) wherein R^(z1)is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In some such embodiments, R^(2g)is halogen. In some such embodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))—C₁-C₆alkylenyl-R^(5a); R^(5d) is SO₂R^(5aa); R^(5aa) is C₁-C₃ alkyl or—(C₁-C₃ alkylenyl)-G¹; R^(5a) is G¹ wherein G¹ is phenyl, naphthyl,C₃-C₆ cycloalkyl, heteroaryl, or heterocycle; each of which isoptionally substituted; and R⁴ is H. In some such embodiments, R⁶ is H.In some such embodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃haloalkyl. In some such embodiments, R^(2g) is halogen. In some suchembodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))—C₁-C₆alkylenyl-R^(5a); R^(5d) is SO₂R^(5aa); R^(5aa) is —(C₁-C₃ alkylenyl)-G¹wherein G¹ is optionally substituted phenyl; R^(5a) is G¹ wherein G¹ isoptionally substituted phenyl or optionally substituted cyclopropyl; andR⁴ is H. In some such embodiments, R⁶ is H. In some such embodiments,R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or —OR^(z1)wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In some suchembodiments, R^(2g) is halogen. In some such embodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))C(O)—C₁-C₆alkylenyl-R^(5b); and R⁴ is H. In some such embodiments, R⁶ is H. Insome such embodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl,—CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl.In some such embodiments, R^(2g) is halogen. In some such embodiments,R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))C(O)—C₁-C₆alkylenyl-R^(5b); R^(5d) is H, C₁-C₃ alkyl, or —(C₁-C₆ alkylenyl)-G¹;R^(5b) is G¹, —OR^(5aa), —S(O)₂R^(5aa), —NR^(5bb)C(O)R^(5dd),—NR^(5bb)S(O)₂R^(5dd), —C(O)R^(5aa), or —C(O)NR^(5bb)R^(5cc); R^(5aa),R^(5cc), and R^(5dd) are each independently optionally substitutedphenyl or optionally substituted benzyl; R^(5bb) is H or C₁-C₃ alkyl;and R⁴ is H. In some such embodiments, R⁶ is H. In some suchembodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or—OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In somesuch embodiments, R^(2g) is halogen. In some such embodiments, R^(2g) isF.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))C(O)—C₁-C₆alkylenyl-R^(5b); R^(5d) is H; R^(5b) is G¹ wherein G¹ is phenyl,naphthyl, C₃-C₆ cycloalkyl, heterocycle, or heteroaryl, each of which isoptionally substituted; and R⁴ is H. In some such embodiments, R⁶ is H.In some such embodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃haloalkyl. In some such embodiments, R^(2g) is halogen. In some suchembodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ is N(R^(5d))C(O)—C₁-C₆alkylenyl-R⁵b; R^(5d) is H; R⁵ b is G¹ wherein G¹ is optionallysubstituted phenyl or optionally substituted C₅-C₆ heteroaryl; and R⁴ isH. In some such embodiments, R⁶ is H. In some such embodiments, R^(2g)is C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, —CN, or —OR^(z1) whereinR^(z1) is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl. In some such embodiments,R^(2g) is halogen. In some such embodiments, R^(2g) is F.

In one embodiment, the invention is directed to compounds of formula(I), wherein R¹ is methyl, Y¹ is CR⁴, R³ is —O—C₁-C₃ alkyl, A² is CR⁵,A¹, A³, and A⁴ are CR⁶, L is O, G² is phenyl which is optionallysubstituted with 1, 2, or 3 R^(2g) groups; R⁵ isN(R^(5d))C(O)N(R^(5d))-G¹; and R⁴ is H. In some such embodiments, R⁶ isH. In some such embodiments, R^(2g) is C₁-C₃ alkyl, halogen, C₁-C₃haloalkyl, —CN, or —OR^(z1) wherein R^(z1) is H, C₁-C₃ alkyl, or C₁-C₃haloalkyl. In some such embodiments, R^(2g) is halogen. In some suchembodiments, R^(2g) is F.

Compounds of formula (I) may contain one or more asymmetricallysubstituted atoms. Compounds of formula (I) may also exist as individualstereoisomers (including enantiomers and diastereomers) and mixturesthereof. Individual stereoisomers of compounds of formula (I) may beprepared synthetically from commercially available starting materialsthat contain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution of the individual stereoisomer usingmethods that are known to those of ordinary skill in the art. Examplesof resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

Compounds of formula (I) may also include the various geometric isomersand mixtures thereof resulting from the disposition of substituentsaround a carbon-carbon double bond, a carbon-nitrogen double bond, acycloalkyl group, or a heterocycle group. Substituents around acarbon-carbon double bond or a carbon-nitrogen double bond aredesignated as being of Z or E configuration and substituents around acycloalkyl or heterocycle are designated as being of cis or transconfiguration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism and alltautomeric isomers are included in the scope of the invention.

Thus, the formula drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formula drawings.

Exemplary compounds of formula (I) include, but are not limited to:

-   2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3,4-dihydro-2H-chromen-6-yl)acetamide;-   2-(4-chloro-2-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(6-methylpyridin-3-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1,5-dimethyl-1H-pyrazol-3-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methyl-1,3-thiazol-5-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-[3-(2-fluorophenyl)-1H-pyrazol-1-yl]acetamide;-   5-[2-(2,4-difluorophenoxy)-5-{[3-(1H-pyrazol-1-yl)propyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-{2-(2,4-difluorophenoxy)-5-[(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[2-(2,4-difluorophenoxy)-5-{[(6-methylpyridin-2-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[2-(2,4-difluorophenoxy)-5-{[(3-methylpyridin-2-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[2-(2,4-difluorophenoxy)-5-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   methyl    4-{[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}butanoate;-   1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3-phenoxyphenyl)urea;-   1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,4-dimethylphenyl)urea;-   1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3,5-dimethylphenyl)urea;-   1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-[4-(trifluoromethoxy)phenyl]urea;-   1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,5-dimethylphenyl)urea;-   1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(4-fluorophenyl)urea;-   1-(3-chlorophenyl)-3-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]urea;-   1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3-methoxyphenyl)urea;-   5-{2-(2,4-difluorophenoxy)-5-[(1,3-oxazol-5-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[2-(2,4-difluorophenoxy)-5-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[2-(2,4-difluorophenoxy)-5-{[(1-ethyl-1H-pyrazol-3-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-5-oxo-5-phenylpentanamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(phenylsulfonyl)propanamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3-phenoxyphenyl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-[4-(methylsulfonyl)phenyl]acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-phenoxypropanamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(naphthalen-1-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-{[(4-methylphenyl)sulfonyl]amino}acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(4-methylphenoxy)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,3,4-trimethoxyphenyl)propanamide;-   2-(benzyloxy)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   2-(1,2-benzoxazol-3-yl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(4-phenoxyphenyl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-phenylbutanamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(naphthalen-2-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N′-phenylpentanediamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-phenylpropanamide;-   2-(biphenyl-4-yl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-oxo-4-phenylbutanamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-phenoxybutanamide;-   2-[4-(benzyloxy)phenyl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methoxyphenyl)acetamide;-   N-(2-{[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}-2-oxoethyl)benzamide;-   2-cyclohexyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   2-[(1S,4R)-bicyclo[2.2.1]hept-2-yl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   5-[5-{[2-(benzyloxy)-3-methoxybenzyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[5-{[4-(benzyloxy)benzyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-{5-[(4-tert-butylbenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-{5-[(2,6-difluorobenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[2-(2,4-difluorophenoxy)-5-{[3-(4-methoxyphenoxy)benzyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[5-({[5-(2-chlorophenyl)furan-2-yl]methyl}amino)-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   4-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile;-   2-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile;-   5-{2-(2,4-difluorophenoxy)-5-[(quinolin-4-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-[5-{[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-{2-(2,4-difluorophenoxy)-5-[({5-[2-(trifluoromethyl)phenyl]furan-2-yl}methyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-{5-[(4-butoxybenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-{2-(2,4-difluorophenoxy)-5-[(4-phenoxybenzyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   3-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile;-   5-{2-(2,4-difluorophenoxy)-5-[(4-fluorobenzyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   5-{5-[(cyclopropylmethyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one;-   1-(2-chloro-5-fluorophenyl)-N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]methanesulfonamide;-   2-(2-chloro-5-fluorophenyl)-N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   N-[4-(benzyloxy)benzyl]-2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(4-fluorobenzyl)acetamide;-   2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]propanamide;-   2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-methylacetamide;-   N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide;-   N-benzyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide;-   N-(2-chlorobenzyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(2-phenylethyl)ethanesulfonamide;-   N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide;-   N-benzyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide;-   N-(2-chlorobenzyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(2-phenylethyl)methanesulfonamide;-   N-[2-(2-chlorophenyl)ethyl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3-phenyl-1H-pyrazol-1-yl)acetamide;-   2-(5-chloro-2-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methyl-1,3-thiazol-4-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1H-pyrazol-1-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(pyrimidin-5-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3,5-dimethyl-1H-pyrazol-1-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1H-1,2,4-triazol-1-yl)acetamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(pyrazin-2-yl)acetamide;-   N-[2-(2-chlorophenyl)ethyl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(1,3-thiazol-2-ylmethyl)methanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyridin-3-ylmethyl)ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyridin-3-ylmethyl)methanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyrimidin-5-ylmethyl)ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyrimidin-5-ylmethyl)methanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyrazin-2-ylmethyl)ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyrazin-2-ylmethyl)methanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-pyrazol-4-yl)methyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-phenylmethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(1,3-thiazol-2-ylmethyl)ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]-1-phenylmethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(2S)-1,4-dioxan-2-ylmethyl]ethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(tetrahydro-2H-pyran-4-ylmethyl)ethanesulfonamide;    and-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]ethanesulfonamide.-   A further embodiment include compounds of formula (I) or    pharmaceutically acceptable salt thereof, wherein the compounds are    selected from the group consisting of

2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide;

-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methyl-1,3-thiazol-5-yl)acetamide;-   N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide;-   N-benzyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide;-   N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide;-   N-benzyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide;-   N-(2-chlorobenzyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(2-phenylethyl)methanesulfonamide;-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3-phenyl-1H-pyrazol-1-yl)acetamide;    and-   N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methyl-1,3-thiazol-4-yl)acetamide.

Compounds of formula (I) may be used in the form of pharmaceuticallyacceptable salts. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge etal. J. Pharmaceutical Sciences, 1977, 66: 1-19.

Compounds of formula (I) may contain either a basic or an acidicfunctionality, or both, and can be converted to a pharmaceuticallyacceptable salt, when desired, by using a suitable acid or base. Thesalts may be prepared in situ during the final isolation andpurification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts may be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Other examples oforganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazineand the like.

The term “pharmaceutically acceptable prodrug” or “prodrug”as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of formula (I) formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

Compounds described herein can exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms for thepurposes of the invention.

General Synthesis

The compounds described herein, including compounds of general formula(I) and specific examples, can be prepared by methodologies known in theart, for example, through the reaction schemes depicted in schemes 1-7.The variables A¹, A², A³, A⁴, R¹, R², R³, R⁴, R⁶, G¹, G², Y¹, Y², andused in the following schemes have the meanings as set forth in thesummary and detailed description sections, unless otherwise noted.

Abbreviations used in the descriptions of the schemes and the specificexamples have the following meanings: DIPEA for diisopropylethylamine,DMA for N,N-dimethylacetamide, DME for 1,2-dimethoxyethane, DMF forN,N-dimethylformamide, DMSO for dimethyl sulfoxide, dppf for1,1′-bis(diphenylphosphino)ferrocene, EDC or EDAC for1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, mesylatefor methyl sulfonate; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HOBT for 1-hydroxybenzotriazole hydrate, HPLC forHigh Performance Liquid chromatography, Prep HPLC for Preparative HighPerformance Liquid chromatography, MeOH for methanol, TFA fortrifluoroacetic acid, THF for tetrahydrofuran, and tosylate forp-toluene sulfonate.

Compounds of general formula (I) may be prepared using the generalprocedure as outlined in Scheme 1. Conversion of (1), wherein Z is Cl,Br, I, or triflate to compounds of general formula (I) may be achievedby treatment with boronic acids of formula (2) or derivatives thereof(e.g., pinacol ester) under Suzuki coupling conditions (N. Miyama and A.Suzuki, Chem. Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999,576:147-148). For example, the coupling reaction may be conducted in thepresence of a palladium catalyst and a base, and optionally in thepresence of a ligand, and in a suitable solvent at elevated temperature(about 80° C. to about 150° C.). The reaction may be facilitated bymicrowave irradiation. Examples of the palladium catalyst include, butare not limited to, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(triphenylphosphine)palladium(II) dichloride, andpalladium(II)acetate. Examples of suitable bases that may be employedinclude, but not limited to, carbonates, acetates, or phosphates ofsodium, potassium, and cesium, and cesium fluoride. Examples of suitableligands include, but are not limited to,1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), and1,1′-bis(diphenylphosphanyl)ferrocene. Non-limiting examples of suitablesolvent include methanol, ethanol, dimethoxyethane,N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, andwater, or a mixture thereof.

Alternatively, compounds of formula (I) may be synthesized by reactionof boronic acids (4) or derivatives thereof (e.g., pinacol ester) underSuzuki coupling conditions as described above with compounds of formula(5) wherein Z is Br, Cl, I, or triflate.

Intermediates (1) wherein Y¹ is CR⁴, Z is Br, Cl, or I, and R³ is—O—C₁-C₆ alkyl may be prepared as outlined in Scheme 2.

Generally, heteroaryl amines of formula (6) wherein R¹⁰¹ is Br, Cl, or Imay be converted to alcohols of formula (7) by treatment with sodiumnitrite and an acid such as, for example sulfuric acid, in a solventsuch as water, and at a temperature from about 0° C. to about 25° C.

Reaction of compounds of formula (7) with a C₁-C₃ alkyl halide, in thepresence of a base such as carbonate of cesium, sodium, or potassium andin a solvent such as, but not limited to, dimethylformamide,tetrahydrofuran, or dimethylsulfoxide, provides intermediates of formula(8). The reaction may be conducted at temperature such as, but notlimited to, about 25° C. to about 60° C.

Displacement of the chlorine atom of formula (8) with alcohols offormula C₁-C₆ alkyl-OH provides compounds of formula (1a). Displacementof the chlorine atom may be accomplished in a solvent such as, but notlimited to, methanol or ethanol, and in the presence of a base such as,but not limited to, sodium ethoxide or sodium hydride, and at atemperature from about 40° C. to about 80° C.

Boronic acids of formula (2) wherein Y² is —O-G², A¹, A³, and A⁴ areCR⁶, and A² is C—NH₂ may be prepared as illustrated in Scheme 3.

Displacement of the fluorine atom of compounds (9) with alcohols offormula G²OH provides compounds of formula (10). The displacementreaction may be accomplished in a solvent such as, but not limited to,dimethylsulfoxide, dimethylformamide, dioxane, or tetrahydrofuran, andin the presence of a base such as, but not limited to, carbonate ofcesium, sodium, or potassium, or sodium hydride, and at a temperature ofabout 40° C. to about 120° C.

Reduction of compounds (10) to anilines of formula (11) may be achievedwith iron powder in the presence of ammonium chloride in a solvent suchas, but not limited to, tetrahydrofuran, ethanol, or water, or a mixturethereof, and at a temperature from about 80° C. to about 120° C.Alternatively the reduction may be carried out with tin chloride inhydrochloric acid at a temperature from about 80° C. to about 120° C.Transformation of (10) to (11) may also be conducted in the presence ofa catalyst such as platinum oxide or palladium on charcoal, in a solventsuch as ethanol or methanol and under hydrogen pressure.

Treatment of the compounds of formula (11) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) using Suzukicoupling reaction conditions as discussed in Scheme 1 generally affordscompounds of formula (2a).

Transformation of anilines of formula (12) is generally illustrated inScheme 4.

Tertiary sulfonamides of structure (15) wherein R¹⁰² is C₁-C₆alkylenyl-G¹ may be formed by treatment of secondary anilines (14) withsulfonyl chlorides of formula R^(5aa)SO₂Cl, in the presence of a basesuch as triethylamine or diisopropylethylamine and in a solvent such asdichloromethane or tetrahydrofuran, at a temperature from about 0° C. toabout 40° C. Alternatively, sulfonamides of formula (13) may bealkylated by treatment of an alkyl halide of formula R¹⁰²X where X ischloro, bromo, iodo, tosylate or mesylate in the presence of a base suchas sodium hydride or potassium carbonate in a solvent such as DMF ormethanol to provide tertiary sulfonamides of structure (15). Thereaction may be conducted at a temperature from about 40° C. to about180° C., optionally facilitated by microwave irradiation.

As shown in Scheme 5, tertiary amides (18) wherein R¹⁰⁴ is C₁-C₆ alkylor —(C₁-C₆ alkylenyl)-G¹ and R¹⁰³ is —(C₁-C₆ alkylenyl)-G¹ may be formedby treatment of secondary anilines (17) with carboxylic acids of formulaR¹⁰³COOH in the presence of a coupling agent such as HATU or EDAC and abase such as diisopropylethylaminde or triethylamine, and in a solventsuch as dimethylacetamide, tetrahydrofuran, dioxane, ordimethylformamide, at a temperature from about 0° C. to about 100° C.Transformation of secondary anilines (17) to amides (18) may also beaccomplished by treatment of (17) with acid chlorides of formulaR¹⁰³COCl in the presence of a base such as, for example triethylamine,in a solvent such as, for example, dichloromethane, and at about roomtemperature. Alternatively, amides of formula (16) may be alkylated bytreatment of an alkyl halide of formula R¹⁰⁴X where X is chloro, bromo,iodo, tosylate or mesylate in the presence of a base such as sodiumhydride or sodium hydroxide in a solvent such as DMF or dichloromethaneto provide tertiary amides of structure (18).

Treatment of aniline (12) with isocyanates of formula G¹NCO in thepresence of a base such as pyridine, and in a solvent such astetrahydrofuran, dioxane, or dimethylacetamide, at a temperature fromabout 0° C. to about 100° C. provides ureas of formula (19).

Treatment of anilines (12) with aldehydes of formula G¹CHO underreductive amination conditions such as, but not limited to, sodiumcyanoborohydride and acetic acid in a solvent such as, but not limitedto, dimethylacetamide or dichloromethane provides secondary anilines offormula (20).

Amides (16) may be prepared by reaction of amines (12) with acids offormula R¹⁰³COOH or acid chlorides of formula R¹⁰³COCl, employingreaction conditions as discussed in Scheme 5 for the transformation of(17) to (18).

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Synthetic Examples section. Reactions may be further processed inthe conventional manner, e.g. by eliminating the solvent from theresidue and further purified according to methodologies generally knownin the art such as, but not limited to, crystallization, distillation,extraction, trituration and chromatography. Unless otherwise described,the starting materials and reagents are either commercially available ormay be prepared by one skilled in the art from commercially availablematerials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that can not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which canbe found in T. Greene and P. Wuts, Protecting Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention can be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, can be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound is required, it can beobtained by carrying out one of the procedures described herein using anoptically active starting material (prepared, for example, by asymmetricinduction of a suitable reaction step), or by resolution of a mixture ofthe stereoisomers of the compound or intermediates using a standardprocedure (such as chromatographic separation, recrystallization orenzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, itcan be prepared by carrying out one of the above procedures using a puregeometric isomer as a starting material, or by resolution of a mixtureof the geometric isomers of the compound or intermediates using astandard procedure such as chromatographic separation.

Pharmaceutical Compositions

This invention also provides for pharmaceutical compositions comprisinga therapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, diluent, or excipient therefor. Thephrase “pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

The pharmaceutical compositions that comprise a compound of formula (I),alone or or in combination with a second therapeutic agent, may beadministered to the subjects orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol and the like), vegetableoils (such as olive oil), injectable organic esters (such as ethyloleate) and suitable mixtures thereof. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form may be accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In certain embodiments, solid dosage formsmay contain from 1% to 95% (w/w) of a compound of formula (I). Incertain embodiments, the compound of formula (I) may be present in thesolid dosage form in a range of from 5% to 70% (w/w). In such soliddosage forms, the active compound may be mixed with at least one inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate andor a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

The pharmaceutical composition may be a unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampules. Also, the unit dosage form can be a capsule, tablet, cachet, orlozenge itself, or it can be the appropriate number of any of these inpackaged form. The quantity of active component in a unit dosepreparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mgto 100 mg, or from 1% to 95% (w/w) of a unit dose, according to theparticular application and the potency of the active component. Thecomposition can, if desired, also contain other compatible therapeuticagents.

The dose to be administered to a subject may be determined by theefficacy of the particular compound employed and the condition of thesubject, as well as the body weight or surface area of the subject to betreated. The size of the dose also will be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular compound in a particular subject. Indetermining the effective amount of the compound to be administered inthe treatment or prophylaxis of the disorder being treated, thephysician can evaluate factors such as the circulating plasma levels ofthe compound, compound toxicities, andor the progression of the disease,etc. In general, the dose equivalent of a compound is from about 1 μg/kgto 100 mg/kg for a typical subject.

For administration, compounds of the formula (I) may be administered ata rate determined by factors that can include, but are not limited to,the LD₅₀ of the compound, the pharmacokinetic profile of the compound,contraindicated drugs, and the side-effects of the compound at variousconcentrations, as applied to the mass and overall health of thesubject. Administration can be accomplished via single or divided doses.

The compounds utilized in the pharmaceutical method of the invention canbe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In certain embodiments, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Treatment may be initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of formula (I) may also be administered in the form ofliposomes. Liposomes generally may be derived from phospholipids orother lipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals which are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes can be used. The present compositions in liposome formmay contain, in addition to a compound of formula (I), stabilizers,preservatives, excipients and the like. Examples of lipids include, butare not limited to, natural and synthetic phospholipids and phosphatidylcholines (lecithins), used separately or together.

Methods to form liposomes have been described, see example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq.

Dosage forms for topical administration of a compound described hereininclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Methods of Use

The compounds of formula (I), or pharmaceutically acceptable saltsthereof, and pharmaceutical compositions comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, can beadministered to a subject suffering from a bromodomain-mediated disorderor condition. The term “administering” refers to the method ofcontacting a compound with a subject. Thus, the compounds of formula (I)may be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally,parentally, or intraperitoneally. Also, the compounds described hereincan be administered by inhalation, for example, intranasally.Additionally, the compounds of formula (I) may be administeredtransdermally, topically, via implantation, transdermally, topically,and via implantation. In certain embodiments, the compounds of theformula (I) may be delivered orally. The compounds can also be deliveredrectally, bucally, intravaginally, ocularly, andially, or byinsufflation. Bromodomain-mediated disorders and conditions can betreated prophylactically, acutely, and chronically using compounds offormula (I), depending on the nature of the disorder or condition.Typically, the host or subject in each of these methods is human,although other mammals can also benefit from the administration of acompound of formula (I).

A “bromodomain-mediated disorder or condition” is characterized by theparticipation of one or more bromodomains (e.g., BRD4) in the inception,manifestation of one or more symptoms or disease markers, severity, orprogression of a disorder or condition. Accordingly, compounds offormula (I) may be used to treat cancer, including, but not limited toacoustic neuroma, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.

Further, compounds of formula (I) may be used to treat inflammatorydiseases, inflammatory conditions, and autoimmune diseases, including,but not limited to: Addison's disease, acute gout, ankylosingspondylitis, asthma, atherosclerosis, Behcet's disease, bullous skindiseases, cardiac myopathy, chronic obstructive pulmonary disease(COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis,glomerulonephritis, heart failure, hepatitis, hypophysitis, inflammatorybowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis,myocarditis, myositis, nephritis, organ transplant rejection,osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa,pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis,rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis,systemic lupus erythematosus, Takayasu's Arteritis, toxic shock,thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo,vasculitis, and Wegener's granulomatosis.

Compounds of formula (I), or pharmaceutically acceptable salts thereof,may be used to treat AIDS.

The compounds of formula (I) may be co-administered to a subject. Theterm “co-administered” means the administration of two or more differenttherapeutic agents or treatments (e.g., radiation treatment) that areadministered to a subject by combination in the same pharmaceuticalcomposition or separate pharmaceutical compositions. Thusco-administration involves administration at the same time of a singlepharmaceutical composition comprising two or more therapeutic agents oradministration of two or more different compositions to the same subjectat the same or different times.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to treat acancer, where examples of the agents include, such as radiation,alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors,activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE(Bi-Specific T cell Engager) antibodies, antibody drug conjugates,biologic response modifiers, cyclin-dependent kinase inhibitors, cellcycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (dual variabledomain antibodies), leukemia viral oncogene homolog (ErbB2) receptorinhibitors, growth factor inhibitors, heat shock protein (HSP)-90inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies,immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs),intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2inhibitors, mammalian target of rapamycin inhibitors, microRNA's,mitogen-activated extracellular signal-regulated kinase inhibitors,multivalent binding proteins, non-steroidal anti-inflammatory drugs(NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP)inhibitors, platinum chemotherapeutics, polo-like kinase (Plk)inhibitors, phosphoinositide-3 kinase (bromodomain) inhibitors,proteosome inhibitors, purine analogs, pyrimidine analogs, receptortyrosine kinase inhibitors, etinoidsdeltoids plant alkaloids, smallinhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,ubiquitin ligase inhibitors, and the like, and in combination with oneor more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability andor increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, singledouble strands, bulges,nicksgaps, mismatches) and are processed in cells to provide active genesilencing. A double-stranded siRNA (dsRNA) can have the same number ofnucleotides on each strand (blunt ends) or asymmetric ends (overhangs).The overhang of 1-2 nucleotides can be present on the sense andor theantisense strand, as well as present on the 5′- and or the 3′-ends of agiven strand.

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN®(melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include ABT-199, AT-101 ((-)gossypol),GENASENSE® (G3139 or oblimersen (Bcl-2-targeting antisenseoligonucleotide)), IPI-194, IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFRimmunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgAantibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like.

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DRS) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMATM(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine)(ONCOVIN®; P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EP0906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTATAAE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents to treat aninflammatory disease or condition, or autoimmune disease, where examplesof the agents include, such as methotrexate, 6-mercaptopurine,azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquine, pencillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled and local injection), beta-2 adrenoreceptor agonists(salbutamol, terbutaline, salmeteral), xanthines (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such asprednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1βconverting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (etanercept) and p55TNFRIgG(Lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen,valdecoxib, sulfasalazine, methylprednisolone, meloxicam,methylprednisolone acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, prednisolone, morphine sulfate, lidocaine hydrochloride,indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol,naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP,MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469,VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists(such as FTY720), PKC family inhibitors (such as Ruboxistaurin orAEB-071) and Mesopram. In certain embodiments, combinations includemethotrexate or leflunomide and in moderate or severe rheumatoidarthritis cases, cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of formula (I) of the invention may beco-administered include the following: budenoside; epidermal growthfactor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates;6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors;mesalamine; olsalazine; balsalazide; antioxidants; thromboxaneinhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies;anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors;pyridinyl-imidazole compounds; antibodies to or antagonists of otherhuman cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide;NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone;phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents;complement inhibitors; adrenergic agents; agents which interfere withsignalling by proinflammatory cytokines such as TNFα or IL-1 (e.g. NIK,IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors; TNFαconverting enzyme inhibitors; T-cell signalling inhibitors such askinase inhibitors; metalloproteinase inhibitors; sulfasalazine;azathioprine; 6-mercaptopurines; angiotensin converting enzymeinhibitors; soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ).Preferred examples of therapeutic agents for Crohn's disease with whicha compound of formula (I) may be combined include the following: TNFantagonists, for example, anti-TNF antibodies, D2E7 (adalimumab), CA2(infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (etanercept) andp55TNFRIgG (LENERCEPT™) inhibitors and PDE4 inhibitors. A compound offormula (I) may be combined with corticosteroids, for example,budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1β convertingenzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolonesodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of formula (I) may be co-administered include thefollowing: corticosteroids; prednisolone; methylprednisolone;azathioprine; cyclophosphamide; cyclosporine; methotrexate;4-aminopyridine; tizanidine; interferon-β1a (AVONEX®; Biogen);interferon-β1b (BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of formula (I) cmay be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. A compound of formula (I) may also be combined with agents suchas methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adensosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

A compound of formula (I) may also be co-administered with agents, suchas alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of formula (I) may be co-administered include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, D2E7 (HUMIRA®), CA2 (infliximab), CDP 571, TNFR-Igconstructs, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (LENERCEPT®).

Non-limiting examples of therapeutic agents for asthma with which acompound of formula (I) may be co-administered include the following:albuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of formula (I) may be co-administered include the following:albuterol sulfate/ipratropium, ipratropium bromide,salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasonepropionate, prednisone, theophylline anhydrous, methylprednisolonesodium succinate, montelukast sodium, budesonide, formoterol fumarate,triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxonesodium, amoxicillin trihydrate, gatifloxacin, zafirlukast,amoxicillin/clavulanate, flunisolide/menthol,chlorpheniramine/hydrocodone, metaproterenol sulfate,methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate,tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of formula (I) may be co-administered include the following:calcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen,salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of formula (I) may be co-administered include thefollowing: methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), andefalizumab.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of formula (I) may be co-administered include the following:NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam,indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib,valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids,for example, prednisone, prednisolone, budenoside, dexamethasone;cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolatemofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor,for example Cellcept®. A compound of formula (I) may also be combinedwith agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine,Imuran® and agents which interfere with synthesis, production or actionof proinflammatory cytokines such as IL-1, for example, caspaseinhibitors like IL-1β converting enzyme inhibitors and IL-1ra. Acompound of formula (I) may also be used with T cell signalinginhibitors, for example, tyrosine kinase inhibitors; or molecules thattarget T cell activation molecules, for example, CTLA-4-IgG or anti-B7family antibodies, anti-PD-1 family antibodies. A compound of formula(I) may be combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. A compound of formula (I) may also be usedwith LJP 394 (abetimus), agents that deplete or inactivate B-cells, forexample, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlySantibody), TNF antagonists, for example, anti-TNF antibodies, D2E7(adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG(etanercept) and p55TNFRIgG (LENERCEPT™).

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in theprevention or treatment of AIDS, where examples of the agents include,HIV reverse transcriptase inhibitors, HIV protease inhibitors,immunomodulators, and other retroviral drugs. Examples of reversetranscriptase inhibitors include, but are not limited to, abacavir,adefovir, didanosine, dipivoxil delavirdine, efavirenz, lamivudine,nevirapine, stavudine zalcitabine, and zidovudine. Examples of proteaseinhibitors include, but are not limited to, amprenavir, indinavir,lopinavir, nelfinavir, ritonavir, and saquinavir.

The following Examples may be used for illustrative purposes and shouldnot be deemed to narrow the scope of the invention.

EXAMPLES Example 12-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamideExample 1A 5-bromo-4-chloropyridin-2-ol

5-Bromo-4-chloropyridin-2-amine (2.01 g, 9.69 mmol) was dissolved in 75%(v/v) sulfuric acid (40.2 mL, 566 mmol) and then chilled in an ice bath.A solution of sodium nitrite (2.21 g, 32.0 mmol) in water (20.1 mL, 1116mmol) was added drop-wise and the reaction mixture was then stirred for3 hours. The mixture was concentrated under reduced pressure and aqueousammonia (15 mL) was added drop-wise. The resulting white precipitate wascollected via vacuum filtration and the filter cake washed with coldwater (100 mL) then dried in a vacuum oven for 24 hours to give 1.94 g(95%) of the title compound.

Example 1B 5-bromo-4-chloro-1-methylpyridin-2(1H)-one

A flask fitted with a stir bar was charged with Example 1A (27.45 g, 132mmol), cesium carbonate (51.53 g, 158 mmol) and DMF (325 mL). Methyliodide (10 mL, 160 mmol) was added drop-wise to the suspension and themixture stirred at ambient temperature for 1 hour. The mixture waspoured into a separatory funnel containing 1:1 saturated aqueous sodiumchloride:water (1000 mL) and extracted with ethyl acetate (1000 mL). Theorganics were washed with saturated aqueous sodium chloride, dried(anhydrous magnesium sulfate), filtered, concentrated, and thentriturated with 100 mL of 10% ethyl acetateheptane. The solids werecollected and vacuum dried to provide the title compound.

Example 1C 5-bromo-4-ethoxy-1-methylpyridin-2(1H)-one

A flask with stirbar was charged with Example 1B (3.29 g, 14.79 mmol) inethanol (80 mL). Sodium ethoxide (21 wt %, 9.65 g, 29.8 mmol) was addedand the solution was heated at 80° C. for 70 minutes. The solution wascooled, reduced in volume by rotary evaporation, and then shaken in aseparatory funnel with ethyl acetate (200 mL) and saturated aqueoussodium chloride (200 mL) sequentially. The organics were dried overanhydrous sodium sulfate. After filtration and solvent removal theresidues were chromatographed on a 40 g silica cartridge eluting with0-100% ethyl acetateheptane to provide the title compound.

Example 1D 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene

2-Bromo-1-fluoro-4-nitrobenzene (15 g, 68.2 mmol), 2,4-difluorophenol(7.82 mL, 82 mmol), and cesium carbonate (26.7 g, 82 mmol) were combinedin DMSO (75 mL), heated at 110° C. for 1 hour, and then cooled. To thecooled reaction mixture was added water (1000 mL) and saturated aqueoussodium chloride (1000 mL). The mixture was extracted with ethyl acetate(3×200 mL). The combined organics were washed with saturated aqueoussodium chloride, dried (anhydrous magnesium sulfate), filtered, andconcentrated under reduced pressure to give a crude solid which was usedin the next step without additional purification.

Example 1E 3-bromo-4-(2,4-difluorophenoxy)aniline

A mixture of Example 1D (22.5 g, 68.2 mmol), iron powder (19.0 g, 341mmol), and ammonium chloride (7.30 g, 136 mmol) in tetrahydrofuran (117mL), ethanol (117 mL), and water (39 mL) was refluxed at 100° C. for 2hours. The mixture was cooled just below reflux, and filtered throughCelite. The filter cake was washed with warm methanol (3×50 mL). Thesolution was concentrated under reduced pressure, neutralized to a pH ofabout 8 with saturated NaHCO₃ (150 mL), and extracted with ethyl acetate(3×100 mL). The combined organics were washed with saturated aqueoussodium chloride, dried (anhydrous magnesium sulfate), filtered,concentrated, and purified by flash chromatography (silica gel, 0-15%ethyl acetatehexane gradient) to provide the title compound.

Example 1F4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Example 1E (14.3 g, 47 7 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (24 g, 95mmol), potassium acetate (10.3 g, 105 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (1.39 g,4.77 mmol), and tris(dibenzylideneacetone)dipalladium(0) (1.31 g, 1.43mmol) were degassed under argon for 30 minutes. Dioxane (200 mL),degassed with argon for 30 minutes, was then added by cannula transfer.The reaction mixture was heated at 80° C. for 22 hours. The cooledmixture was vacuum filtered through Celite, rinsed with ethyl acetate(100 mL), and washed with saturated aqueous sodium chloride (150 mL) andwater (150 mL) sequentially. The aqueous phase was extracted with ethylacetate (3×150 mL). The combined organics were washed with saturatedaqueous sodium chloride, dried (anhydrous magnesium sulfate), gravityfiltered, and then concentrated under reduced pressure. Purification byflash chromatography (silica gel, 0-25% ethyl acetatehexane gradient)afforded the title compound.

Example 1G5-[5-amino-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

A 100 mL microwave reaction vessel fitted with a stir bar was chargedwith Example 1C (1.49 g, 6.42 mmol), Example 1F (3.11 g, 8.96 mmol),cesium fluoride (2.99 g, 19.68 mmol), palladiumtetrakistriphenylphosphine (0.273 g, 0.236 mmol) in DME (17.00mL)methanol (8.5 mL), and sealed. The mixture was heated at 90° C. for45 minutes in a Ethos Microsynth multimode microwave reactor (MilestoneInc.), and then cooled to ambient temperature. The reaction mixture wasshaken in a separatory funnel with 300 mL each of saturated aqueoussodium chloride and ethyl acetate. The organics were washed withsaturated aqueous sodium chloride and dried over sodium sulfate. Afterfiltration and solvent removal, the residues were adsorbed on a on a 220g silica cartridge, and eluted with 0-2-10% methanol/dichloromethane toprovide the title compound.

Example 1H2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

A solution of Example 1G and DIPEA (0.182 M and 0.52 M in DMA,respectively, 221 μL, 0.40 mmol Example 1G (1.0 equivalent) and 1.21mmol DIPEA (3.0 equivalents)), HATU (0.182 M in DMA, 221 μL, 0.40 mmol,1 equivalent) and 2-(2-chloro-5-fluorophenyl)acetic acid (0.40 M in DMA,151 μL, 0.60 mmol, 1.5 equivalents) were mixed through a perfluoroalkoxymixing tube (0.2 mm inner diameter), and loaded into an injection loop.The reaction segment was injected into the flow reactor (Hastelloy coil,0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., andpassed through the reactor at 180 μL min⁻¹ (10 minute residence time).Upon exiting the reactor, the solution was loaded directly into aninjection loop and purified by preparative HPLC on a Phenomenex LunaC8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm), eluting with a gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flowrate of 30 mL/min (0-0.5 min 5% A, 0.5-6 5 min linear gradient 5-100% A,6.5-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A, 9.0-10 min 5%A) to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 10.37(s, 1H), 7.59-7.46 (m, 4H), 7.37-7.27 (m, 2H), 7.18 (td, J=8.5, 3.1 Hz,1H), 7.14-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92 (q,J=7.0 Hz, 2H), 3.85 (s, 2H), 3.36 (s, 3H), 1.14 (t, J=7.0 Hz, 3H). MS(APCI+) m/z 543.0 (M+H)⁺.

Example 2N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3,4-dihydro-2H-chromen-6-yl)acetamide

Example 2 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(chroman-6-yl)acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ10.23 (s, 1H), 7.58-7.49 (m, 3H), 7.32 (ddd, J=11.2, 8.6, 2.7 Hz, 1H),7.06-6.84 (m, 5H), 6.70-6.64 (m, 1H), 5.82 (s, 1H), 4.13-4.06 (m, 2H),3.92 (q, J=7.0 Hz, 2H), 3.48 (s, 2H), 3.36 (s, 3H), 2.71 (t, J=6.4 Hz,2H), 1.99-1.85 (m, 2H), 1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 549.0(M+H)⁺.

Example 32-(4-chloro-2-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 3 was prepared according to the procedure used for thepreparation of Example 1H, substituting2-(5-chloro-2-fluorophenyl)acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ10.35 (s, 1H), 7.59-7.49 (m, 2H), 7.46-7.35 (m, 1H), 7.37-7.24 (m, 1H),7.12-6.93 (m, 1H), 6.89 (d, J=8.6 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=7.0Hz, 1H), 3.36 (s, 2H), 1.15 (s, 1H), 1.13 (d, J=6.9 Hz, 2H). MS (APCI+)m/z 543.0 (M+H)⁺.

Example 4N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)acetamide

Example 4 was prepared according to the procedure used for thepreparation of Example 1H, substituting2-(1-methyl-1H-pyrazol-4-yl)acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid to provide the title compound asa trifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.59 (s, 1H),7.58-7.49 (m, 3H), 7.38-7.27 (m, 2H), 7.10-6.92 (m, 2H), 6.89 (d, J=8.5Hz, 1H), 5.82 (s, 1H), 3.98-3.88 (m, 2H), 3.45 (s, 2H), 3.37 (s, 3H),1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 495.0 (M+H)⁺.

Example 5N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(6-methylpyridin-3-yl)acetamide

Example 5 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(6-methylpyridin-3-yl)aceticacid for 2-(2-chloro-5-fluorophenyl)acetic acid to provide the titlecompound as a trifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ8.70 (d, J=2.0 Hz, 1H), 8.41 (dd, J=8.2, 2.0 Hz, 1H), 7.90 (d, J=8.2 Hz,1H), 7.58-7.49 (m, 3H), 7.33 (ddd, J=11.2, 8.6, 2.7 Hz, 1H), 7.15-6.93(m, 2H), 6.90 (d, J=8.6 Hz, 1H), 5.83 (s, 1H), 3.98-3.85 (m, 4H), 3.37(s, 3H), 2.72 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 506.0(M+H)⁺.

Example 6N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1,5-dimethyl-1H-pyrazol-3-yl)acetamide

Example 6 was prepared according to the procedure used for thepreparation of Example 1H, substituting2-(1,5-dimethyl-1H-pyrazol-3-yl)acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid to provide the title compound asa trifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.59-7.49 (m,3H), 7.32 (ddd, J=11.2, 8.6, 2.7 Hz, 1H), 7.06-6.92 (m, 2H), 6.89 (d,J=8.6 Hz, 1H), 5.99 (s, 1H), 5.83 (s, 1H), 3.92 (q, J=7.0 Hz, 2H), 3.51(s, 2H), 3.37 (s, 3H), 2.21 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (APCI+)m/z 509.0 (M+H)⁺.

Example 7N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methyl-1,3-thiazol-5-yl)acetamide

Example 7 was prepared according to the procedure used for thepreparation of Example 1H, substituting2-(2-methyl-1,3-thiazol-5-yl)acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid to provide the title compound. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ 7.60-7.48 (m, 4H), 7.33 (ddd, J=11.2, 8.6,2.7 Hz, 1H), 7.10-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.83 (s, 1H),3.93 (q, J=7.0 Hz, 4H), 3.90-3.87 (m, 2H), 3.37 (s, 3H), 1.14 (t, J=6.9Hz, 3H). MS (APCI+) m/z 512.0 (M+H)⁺.

Example 8N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-[3-(2-fluorophenyl)-1H-pyrazol-1-yl]acetamide

Example 8 was prepared according to the procedure used for thepreparation of Example 1H, substituting2-[3-(2-fluorophenyl)-1H-pyrazol-1-yl]acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid to provide the title compound asa trifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.93-7.85 (m,2H), 7.60-7.51 (m, 3H), 7.42-7.26 (m, 3H), 7.25 (d, J=7.5 Hz, 1H),7.07-6.88 (m, 3H), 6.69 (dd, J=3.8, 2.3 Hz, 1H), 5.82 (s, 1H), 5.09 (s,2H), 3.92 (q, J=7.0 Hz, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS(APCI+) m/z 575.0 (M+H)⁺.

Example 95-[2-(2,4-difluorophenoxy)-5-{[3-(1H-pyrazol-1-yl)propyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

A stock solution of Example 1G (0.167 M in methanol, 392 μL, 0.065 mmol,1.0 equivalent), acetic acid (4 M in methanol, 162 μL, 0.65 mmol, 10equivalents), NaBH₃CN (0.6 M in methanol, 162 μL, 0.097 mmol, 1.5equivalents) and 3-(1H-pyrazol-1-yl)propanal (0.40 M in DMA, 195 μL,0.078 mmol, 1.2 equivalents) were aspirated from their respective sourcevials, mixed through a perfluoroalkoxy mixing tube (0.2 mm innerdiameter), and loaded into an injection loop. The reaction segment wasinjected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter,2.32 mL internal volume) set at 100° C., and passed through the reactorat 232 μL min⁻¹ (10 minute residence time). Upon exiting the reactor,the reaction was loaded directly into an injection loop and purified bypreparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (50mm×21.2 mm) eluting with a gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) at a flow rate of 30 mL/min (0-0.5 min5% A, 0.5-6.5 min linear gradient 5-100% A, 6.5-8.5 min 100% A, 8.5-9.0min linear gradient 100-5% A, 9.0-10 min 5% A) to provide the titlecompound as the trifluoroacetate salt. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.64 (d, J=2.2 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.36 (s, 1H), 7.11 (ddd,J=11.3, 8.6, 2.8 Hz, 1H), 6.91-6.76 (m, 3H), 6.60 (dd, J=8.7, 2.9 Hz,1H), 6.51 (d, J=2.8 Hz, 1H), 6.22 (t, J=2.0 Hz, 1H), 5.74 (s, 1H), 4.21(t, J=6.8 Hz, 2H), 3.90 (q, J=6.9 Hz, 2H), 3.03 (t, J=6.9 Hz, 2H), 2.07(p, J=6.9 Hz, 2H), 1.15 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 481.1 (M+H)⁺.

Example 105-{2-(2,4-difluorophenoxy)-5-[(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

The trifluoroacetate salt of Example 10 was prepared according to theprocedure used for the preparation of Example 9, substituting6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carbaldehyde for3-(1H-pyrazol-1-yl)propanal. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.41 (s,1H), 7.35 (s, 1H), 7.13 (ddd, J=11.3, 8.6, 2.8 Hz, 1H), 6.93-6.77 (m,3H), 6.71-6.58 (m, 2H), 5.75 (s, 1H), 4.30 (bs, 2H), 4.17 (t, J=7.2 Hz,2H), 3.91 (q, J=6.9 Hz, 2H), 3.15-3.07 (m, 2H), 2.73-2.62 (m, 2H), 1.14(t, J=6.9 Hz, 3H). MS (APCI+) m/z 493.1 (M+H)⁺.

Example 115-[2-(2,4-difluorophenoxy)-5-{[(6-methylpyridin-2-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

The trifluoroacetate salt of Example 11 was prepared according to theprocedure used for the preparation of Example 9, substituting6-methylpicolinaldehyde for 3-(1H-pyrazol-1-yl)propanal. ¹H NMR (400MHz, DMSO-d₆/D₂O) δ 8.00 (t, J=7.7 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.44(d, J=7.8 Hz, 1H), 7.34 (s, 1H), 7.19-7.06 (m, 1H), 6.94-6.75 (m, 3H),6.65 (dd, J=8.6, 2.9 Hz, 1H), 6.60 (d, J=2.9 Hz, 1H), 5.74 (s, 1H), 4.47(s, 1H), 3.97-3.84 (m, 2H), 1.20-1.12 (m, 2H), 1.11 (d, J=6.9 Hz, 2H).MS (APCI+) m/z 478.1 (M+H)⁺.

Example 125-[2-(2,4-difluorophenoxy)-5-{[(3-methylpyridin-2-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

The trifluoroacetate salt of Example 12 was prepared according to theprocedure used for the preparation of Example 9, substituting3-methylpicolinaldehyde for 3-(1H-pyrazol-1-yl)propanal. ¹H NMR (400MHz, DMSO-d₆/D₂O) δ 8.67-8.41 (m, 1H), 7.99-7.92 (m, 1H), 7.61-7.46 (m,1H), 7.41-7.33 (m, 1H), 7.17-7.07 (m, 1H), 6.95-6.61 (m, 7H), 5.75 (s,1H), 4.61-4.41 (m, 2H), 3.90 (q, J=7.0 Hz, 2H), 1.14 (t, J=6.9 Hz, 3H).MS (APCI+) m/z 478.1 (M+H)⁺.

Example 135-[2-(2,4-difluorophenoxy)-5-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

The trifluoroacetate salt of Example 13 was prepared according to theprocedure used for the preparation of Example 9, substituting1-methyl-1H-pyrazole-5-carbaldehyde for 3-(1H-pyrazol-1-yl)propanal. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ 7.35 (s, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.11(ddd, J=11.3, 8.6, 2.8 Hz, 1H), 6.92-6.73 (m, 2H), 6.69 (dd, J=8.7, 2.9Hz, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.19 (d, J=1.8 Hz, 1H), 5.74 (s, 1H),4.29 (s, 1H), 3.90 (q, J=6.9 Hz, 1H), 3.80 (s, 2H), 1.16 (s, 1H), 1.14(d, J=6.9 Hz, 2H). MS (APCI+) m/z 467.1 (M+H)⁺.

Example 14 methyl4-{[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}butanoate

The trifluoroacetate salt of Example 14 was prepared according to theprocedure used for the preparation of Example 9, substituting methyl4-oxobutanoate for 3-(1H-pyrazol-1-yl)propanal. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.36 (s, 1H), 7.11 (ddd, J=11.3, 8.6, 2.8 Hz, 1H),6.91-6.77 (m, 3H), 6.62 (dd, J=8.7, 2.9 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H),5.74 (s, 1H), 3.91 (q, J=6.9 Hz, 2H), 3.60 (s, 3H), 3.06 (t, J=6.9 Hz,2H), 2.40 (t, J=7.3 Hz, 2H), 1.83 (p, J=7.1 Hz, 2H), 1.16 (t, J=6.9 Hz,3H). MS (APCI+) m/z 473.1 (M+H)⁺.

Example 151-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3-phenoxyphenyl)urea

A stock solution of Example 1G (0.73 M in pyridine, 458 μL, 0.033 mmol,1.0 equivalent) and 1-isocyanato-3-phenoxybenzene (0.40 M in DMA, 108μL, 0.043 mmol, 1.3 equivalents) were aspirated from their respectivesource vials, mixed through a perfluoroalkoxy mixing tube (0.2 mm innerdiameter), and loaded into an injection loop. The reaction segment wasinjected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter,2.32 mL internal volume) set at 100° C., and passed through the reactorat 232 μL min⁻¹ (10 minute residence time). Upon exiting the reactor,the reaction was loaded directly into an injection loop and purified bypreparative HPLC on a Phenomenex Luna C8(2) 5 um 100 Å AXIA column (50mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A,0.5-6.5 min linear gradient 30-70% A, 6.5-7.0 min linear gradient70-100% A, 7.0-8.5 min 100% A, 8.5-9.0 min linear gradient 100-5% A,9.0-10 min 5% A) to yield the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.56 (s, 1H), 7.45-7.37 (m, 3H), 7.39-7.22 (m, 4H),7.20-7.12 (m, 1H), 7.11 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.05-6.92 (m,4H), 6.89 (d, J=8.7 Hz, 1H), 6.63 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 5.82(s, 1H), 3.92 (q, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz, 3H).MS (APCI+) m/z 583.7 (M+H)⁺.

Example 161-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,4-dimethylphenyl)urea

Example 16 was prepared according to the procedure used for thepreparation of Example 15, substituting 1-isocyanato-2,4-dimethylbenzene1-isocyanato-3-phenoxybenzene. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.60-7.53(m, 2H), 7.45 (d, J=2.7 Hz, 1H), 7.41-7.27 (m, 2H), 7.10-6.91 (m, 5H),6.90 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=7.0 Hz, 2H), 3.37 (s,3H), 2.25-2.18 (m, 8H), 1.14 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 519.8(M+H)⁺.

Example 171-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3,5-dimethylphenyl)urea

Example 17 was prepared according to the procedure used for thepreparation of Example 15, substituting 1-isocyanato-3,5-dimethylbenzenefor 1-isocyanato-3-phenoxybenzene. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.57(s, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.41-7.27 (m, 2H), 7.09-6.94 (m, 4H),6.89 (d, J=8.8 Hz, 1H), 6.64 (s, 1H), 5.82 (s, 1H), 3.97-3.88 (m, 2H),3.37 (s, 3H), 2.23 (s, 6H), 1.14 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 519.8(M+H)⁺.

Example 181-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-[4-(trifluoromethoxy)phenyl]urea

Example 18 was prepared according to the procedure used for thepreparation of Example 15, substituting1-isocyanato-4-(trifluoromethoxy)benzene for1-isocyanato-3-phenoxybenzene. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.60-7.52(m, 3H), 7.46-7.36 (m, 2H), 7.36-7.26 (m, 3H), 7.08-6.87 (m, 3H), 5.82(s, 1H), 3.93 (q, J=7.0 Hz, 2H), 3.37 (s, 3H), 1.15 (t, J=6.9 Hz, 3H).MS (APCI+) m/z 576.0 (M+H)⁺.

Example 191-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,5-dimethylphenyl)urea

Example 19 was prepared according to the procedure used for thepreparation of Example 15, substituting 2-isocyanato-1,4-dimethylbenzenefor 1-isocyanato-3-phenoxybenzene. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.62-7.56 (m, 2H), 7.47 (d, J=2.7 Hz, 1H), 7.40-7.26 (m, 2H), 7.10-6.92(m, 3H), 6.90 (d, J=8.7 Hz, 1H), 6.80 (dd, J=7.5, 1.8 Hz, 1H), 5.82 (s,1H), 3.93 (q, J=6.9 Hz, 2H), 3.37 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H),1.14 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 519.8 (M+H)⁺.

Example 201-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(4-fluorophenyl)urea

Example 20 was prepared according to the procedure used for thepreparation of Example 15, substituting 1-fluoro-4-isocyanatobenzene for1-isocyanato-3-phenoxybenzene.

¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.57 (s, 1H), 7.50-7.27 (m, 5H),7.17-7.08 (m, 2H), 7.06-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.82 (s,1H), 3.93 (q, J=6.9 Hz, 2H), 3.37 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS(APCI+) m/z 510.1 (M+H)⁺.

Example 211-(3-chlorophenyl)-3-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]urea

Example 21 was prepared according to the procedure used for thepreparation of Example 15, substituting 1-chloro-3-isocyanatobenzene for1-isocyanato-3-phenoxybenzene.

¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.69 (t, J=2.0 Hz, 1H), 7.58 (s, 1H),7.45 (d, J=2.7 Hz, 1H), 7.39 (dd, J=8.7, 2.7 Hz, 1H), 7.36-7.24 (m, 3H),7.06-6.94 (m, 3H), 6.90 (d, J=8.7 Hz, 1H), 5.83 (s, 1H), 3.93 (q, J=6.9Hz, 2H), 3.37 (s, 3H), 1.15 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 526.1(M+H)⁺.

Example 221-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3-methoxyphenyl)urea

Example 22 was prepared according to the procedure used for thepreparation of Example 15, substituting 1-isocyanato-3-methoxybenzenefor 1-isocyanato-3-phenoxybenzene. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.58(s, 1H), 7.44 (d, J=2.7 Hz, 1H), 7.41-7.27 (m, 2H), 7.23-7.15 (m, 2H),7.06-6.94 (m, 2H), 6.96-6.87 (m, 2H), 6.61-6.54 (m, 1H), 5.82 (s, 1H),3.93 (q, J=6.9 Hz, 2H), 3.37 (s, 3H), 1.15 (t, J=6.9 Hz, 3H). MS (APCI+)m/z 522.1 (M+H)⁺.

Example 235-{2-(2,4-difluorophenoxy)-5-[(1,3-oxazol-5-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

The trifluoroacetate salt of Example 23 was prepared according to theprocedure used for the preparation of Example 9, substitutingoxazole-5-carbaldehyde for 3-(1H-pyrazol-1-yl)propanal. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.14 (s, 1H), 7.35 (s, 1H), 7.11 (ddd, J=11.3, 8.6, 2.8Hz, 1H), 7.01 (d, J=−0.9 Hz, 1H), 6.91-6.76 (m, 2H), 6.68 (dd, J=8.6,2.9 Hz, 1H), 6.60 (d, J=2.9 Hz, 1H), 5.74 (s, 1H), 4.34 (s, 1H),3.94-3.86 (m, 1H), 1.16 (s, 1H), 1.13 (d, J=6.9 Hz, 2H). MS (APCI+) m/z454.1 (M+H)⁺.

Example 245-[2-(2,4-difluorophenoxy)-5-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

The trifluoroacetate salt of Example 24 was prepared according to theprocedure used for the preparation of Example 9, substituting1-methyl-1H-imidazole-5-carbaldehyde for 3-(1H-pyrazol-1-yl)propanal. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ 8.86 (s, 1H), 7.47 (s, 1H), 7.36 (s, 1H),7.12 (ddd, J=11.3, 8.6, 2.8 Hz, 1H), 6.93-6.77 (m, 3H), 6.72 (dd, J=8.7,2.9 Hz, 1H), 6.65 (d, J=2.9 Hz, 1H), 5.75 (s, 1H), 4.38 (s, 2H),3.94-3.88 (m, 2H), 3.87 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (APCI+) m/z467.1 (M+H)⁺.

Example 255-[2-(2,4-difluorophenoxy)-5-{[(1-ethyl-1H-pyrazol-3-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

The trifluoroacetate salt of Example 25 was prepared according to theprocedure used for the preparation of Example 9, substituting1-ethyl-1H-pyrazole-3-carbaldehyde for 3-(1H-pyrazol-1-yl)propanal. ¹HNMR (400 MHz, DMSO-d₆/D₂O) δ 7.55 (d, J=2.2 Hz, 1H), 7.34 (s, 1H), 7.11(ddd, J=11.3, 8.6, 2.8 Hz, 1H), 6.91-6.73 (m, 3H), 6.70 (dd, J=8.7, 2.8Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.17 (d, J=2.2 Hz, 1H), 5.74 (s, 1H),4.20 (s, 2H), 4.07 (q, J=7.2 Hz, 2H), 3.90 (q, J=6.9 Hz, 2H), 1.35 (t,J=7.2 Hz, 3H), 1.15 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 481.1 (M+H)⁺.

Example 26N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-5-oxo-5-phenylpentanamide

Example 26 was prepared according to the procedure used for thepreparation of Example 1H, substituting 5-oxo-5-phenylpentanoic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ8.00-7.94 (m, 2H), 7.68-7.49 (m, 6H), 7.32 (ddd, J=11.2, 8.6, 2.7 Hz,1H), 7.08-6.92 (m, 2H), 6.89 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92 (q,J=7.0 Hz, 2H), 3.37 (s, 3H), 3.10 (t, J=7.1 Hz, 2H), 2.41 (t, J=7.3 Hz,2H), 1.95 (p, J=7.2 Hz, 2H), 1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z547.0 (M+H)⁺.

Example 27N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(phenylsulfonyl)propanamide

Example 27 was prepared according to the procedure used for thepreparation of Example 1H, substituting 3-(phenylsulfonyl)propanoic acidfor 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.95-7.89 (m, 2H), 7.80-7.72 (m, 1H), 7.71-7.63 (m, 2H),7.55 (s, 1H), 7.48-7.40 (m, 2H), 7.36-7.27 (m, 1H), 7.06-6.93 (m, 2H),6.88 (d, J=8.5 Hz, 1H), 5.83 (s, 1H), 3.92 (q, J=6.9 Hz, 2H), 3.61 (t,J=7.2 Hz, 2H), 3.37 (s, 3H), 2.69 (t, J=7.2 Hz, 2H), 1.14 (t, J=6.9 Hz,3H). MS (APCI+) m/z 568.9 (M+H)⁺.

Example 28N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3-phenoxyphenyl)acetamide

Example 28 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(3-phenoxyphenyl)acetic acidfor 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 10.30 (s, 1H), 7.58-7.47 (m, 3H), 7.44-7.27 (m, 4H),7.19-7.08 (m, 2H), 7.10-6.92 (m, 5H), 6.92-6.85 (m, 2H), 5.82 (s, 1H),3.92 (q, J=7.0 Hz, 2H), 3.62 (bs, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz,3H). MS (APCI+) m/z 582.9 (M+H)⁺.

Example 29N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-[4-(methylsulfonyl)phenyl]acetamide

Example 29 was prepared according to the procedure used for thepreparation of Example 1H, substituting 4-(methylsulfonyl)phenylaceticacid for 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.90 (s, 1H), 7.91-7.86 (m, 2H), 7.68-7.50 (m, 5H), 7.32(ddd, J=11.2, 8.6, 2.7 Hz, 1H), 7.09-6.93 (m, 2H), 6.89 (d, J=8.6 Hz,1H), 5.82 (s, 1H), 3.92 (q, J=6.9 Hz, 2H), 3.36 (s, 3H), 3.19 (s, 3H),1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 568.9 (M+H)⁺.

Example 30N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-phenoxypropanamide

Example 30 was prepared according to the procedure used for thepreparation of Example 1H, substituting 3-phenoxypropanoic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.60 (d, J=2.4 Hz, 1H), 7.58-7.51 (m, 2H), 7.36-7.25 (m, 3H), 7.06-6.86(m, 6H), 5.82 (s, 1H), 4.26 (t, J=5.8 Hz, 2H), 3.92 (q, J=6.9 Hz, 2H),3.37 (s, 3H), 2.79 (t, J=5.8 Hz, 2H), 1.14 (t, J=6.9 Hz, 3H). MS (APCI+)m/z 521.0 (M+H)⁺.

Example 31N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(naphthalen-1-yl)acetamide

Example 31 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(naphthalen-1-yl)acetic acidfor 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.13 (d, J=7.3 Hz, 1H), 8.00-7.82 (m, 2H), 7.63-7.45 (m,7H), 7.31 (ddd, J=11.2, 8.6, 2.6 Hz, 1H), 7.06-6.93 (m, 2H), 6.89 (d,J=8.7 Hz, 1H), 5.81 (s, 1H), 4.14 (s, 2H), 3.91 (q, J=6.9 Hz, 2H), 3.35(s, 3H), 1.12 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 541.0 (M+H)⁺.

Example 32N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-{[(4-methylphenyl)sulfonyl]amino}acetamide

Example 32 was prepared according to the procedure used for thepreparation of Example 1H, substituting2-(4-methylphenylsulfonamido)acetic acidfor2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ9.97 (s, 1H), 7.74-7.68 (m, 2H), 7.55 (s, 1H), 7.48-7.27 (m, 5H),7.06-6.93 (m, 2H), 6.91-6.84 (m, 1H), 5.83 (s, 1H), 3.93 (q, J=6.9 Hz,2H), 3.37 (s, 3H), 2.34 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (APCI+) m/z583.5 (M+H)⁺.

Example 33N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(4-methylphenoxy)acetamide

Example 33 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(p-tolyloxy)acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ10.15 (s, 1H), 7.62-7.55 (m, 3H), 7.37-7.28 (m, 1H), 7.15-7.09 (m, 2H),7.09-6.94 (m, 2H), 6.93-6.87 (m, 3H), 5.83 (s, 1H), 4.64 (s, 2H), 3.93(q, J=6.9 Hz, 2H), 3.37 (s, 3H), 2.24 (s, 3H), 1.14 (t, J=6.9 Hz, 3H).MS (APCI+) m/z 521.0 (M+H)⁺.

Example 34N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,3,4-trimethoxyphenyl)propanamide

Example 34 was prepared according to the procedure used for thepreparation of Example 1H, substituting3-(2,3,4-trimethoxyphenyl)propanoic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆D₂O) δ7.60-7.49 (m, 4H), 7.32 (ddd, J=11.2, 8.6, 2.7 Hz, 1H), 7.08-6.84 (m,5H), 6.72 (d, J=8.5 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=7.0 Hz, 3H), 3.37(s, 4H), 2.82 (t, J=7.6 Hz, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (APCI+) m/z595.0 (M+H)⁺.

Example 35 2-(benzyloxy)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 35 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(benzyloxy)acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.62-7.55 (m, 3H), 7.45-7.28 (m, 6H), 7.07-6.86 (m, 3H), 5.83 (s, 1H),4.62 (s, 2H), 4.09 (s, 2H), 3.93 (q, J=6.9 Hz, 2H), 3.37 (s, 3H), 1.14(t, J=6.9 Hz, 3H). MS (APCI+) m/z 521.0 (M+H)⁺.

Example 362-(1,2-benzoxazol-3-yl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 36 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(benzo[d]isoxazol-3-yl)aceticacid for 2-(2-chloro-5-fluorophenyl)acetic acid to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.90 (dt, J=7.9, 1.0 Hz, 1H),7.78-7.71 (m, 1H), 7.68 (ddd, J=8.3, 7.0, 1.3 Hz, 1H), 7.61-7.50 (m,3H), 7.42 (ddd, J=7.9, 6.9, 1.0 Hz, 1H), 7.37-7.28 (m, 1H), 7.07-6.94(m, 2H), 6.91 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 4.16 (s, 2H), 3.92 (q,J=6.9 Hz, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z532.0 (M+H)⁺.

Example 37N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(4-phenoxyphenyl)acetamide

Example 37 was prepared according to the procedure used for thepreparation of Example 1H, substituting 4-phenoxyphenylacetic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.60-7.51 (m, 3H), 7.44-7.24 (m, 5H), 7.18-7.10 (m, 1H), 7.06-6.93 (m,6H), 6.89 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=7.0 Hz, 2H), 3.62(bs, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 582.9(M+H)⁺.

Example 38N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-phenylbutanamide

Example 38 was prepared according to the procedure used for thepreparation of Example 1H, substituting 4-phenylbutanoic acid for2-(2-chloro-5-fluorophenyl)acetic acid.

¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.60-7.49 (m, 3H), 7.38-7.26 (m, 3H),7.25-7.16 (m, 3H), 7.06-6.93 (m, 2H), 6.88 (d, J=8.7 Hz, 1H), 5.82 (s,1H), 3.92 (q, J=6.9 Hz, 2H), 3.37 (s, 3H), 2.62 (t, J=7.6 Hz, 2H), 2.33(t, J=7.3 Hz, 2H), 1.99-1.76 (m, 2H), 1.14 (t, J=6.9 Hz, 3H). MS (APCI+)m/z 519.0 (M+H)⁺.

Example 39N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(naphthalen-2-yl)acetamide

Example 39 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(naphthalen-2-yl)acetic acidfor 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.96-7.85 (m, 3H), 7.85 (s, 1H), 7.63-7.46 (m, 6H),7.36-7.27 (m, 1H), 7.06-6.92 (m, 2H), 6.89 (d, J=8.5 Hz, 1H), 5.81 (s,1H), 3.91 (q, J=6.9 Hz, 2H), 3.35 (s, 3H), 1.12 (t, J=6.9 Hz, 3H). MS(APCI+) m/z 541.0 (M+H)⁺.

Example 40N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N′-phenylpentanediamide

Example 40 was prepared according to the procedure used for thepreparation of Example 1H, substituting 5-oxo-5-(phenylamino)pentanoicacid for 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆D₂O) δ 7.63-7.50 (m, 5H), 7.37-7.26 (m, 3H), 7.12-6.93 (m, 3H),6.89 (d, J=8.6 Hz, 1H), 5.83 (s, 1H), 3.93 (q, J=7.0 Hz, 2H), 3.37 (s,3H), 2.39 (dd, J=7.4, 1.9 Hz, 4H), 2.38-2.35 (m, 2H), 1.99-1.85 (m, 2H),1.14 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 562.0 (M+H)⁺.

Example 41N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-phenylpropanamide

Example 41 was prepared according to the procedure used for thepreparation of Example 1H, substituting 3-phenylpropanoic acid for2-(2-chloro-5-fluorophenyl)acetic acid.

¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 10.05 (s, 1H), 7.60-7.48 (m, 3H),7.40-7.21 (m, 5H), 7.24-7.16 (m, 1H), 7.08-6.93 (m, 2H), 6.88 (d, J=8.6Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=6.9 Hz, 2H), 3.37 (s, 3H), 2.92 (t,J=7.5 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.14 (t, J=6.9 Hz, 3H). MS(APCI+) m/z 505.0 (M+H)⁺.

Example 422-(biphenyl-4-yl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 42 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-([1,1′-biphenyl]-4-yl)aceticacid for 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.69-7.62 (m, 3H), 7.62 (d, J=0.5 Hz, 2H), 7.61-7.50 (m,3H), 7.51-7.42 (m, 4H), 7.40-7.27 (m, 2H), 7.06-6.86 (m, 3H), 5.82 (s,1H), 3.92 (q, J=7.0 Hz, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS(APCI+) m/z 567.0 (M+H)⁺.

Example 43N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-oxo-4-phenylbutanamide

Example 43 was prepared according to the procedure used for thepreparation of Example 1H, substituting 4-oxo-4-phenylbutanoic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ8.03-7.97 (m, 2H), 7.70-7.62 (m, 1H), 7.60-7.44 (m, 5H), 7.36-7.11 (m,1H), 7.13-6.91 (m, 2H), 6.89 (d, J=8.7 Hz, 1H), 5.81 (s, 1H), 3.92 (q,J=7.0 Hz, 2H), 3.36 (s, 4H), 3.33 (d, J=6.2 Hz, 4H), 2.73 (t, J=6.2 Hz,2H), 1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 533.0 (M+H)⁺.

Example 44N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-phenoxybutanamide

Example 44 was prepared according to the procedure used for thepreparation of Example 1H, substituting 4-phenoxybutanoic acid for2-(2-chloro-5-fluorophenyl)acetic acid.

¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.58-7.49 (m, 3H), 7.36-7.24 (m, 3H),7.06-6.85 (m, 6H), 5.82 (s, 1H), 4.01 (t, J=6.2 Hz, 2H), 3.92 (q, J=6.9Hz, 2H), 3.37 (s, 3H), 2.09-1.92 (m, 2H), 1.13 (t, J=6.9 Hz, 3H). MS(APCI+) m/z 535.0 (M+H)⁺.

Example 452-[4-(benzyloxy)phenyl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 45 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-(4-(benzyloxy)phenyl)aceticacid for 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.61-7.49 (m, 3H), 7.50-7.35 (m, 4H), 7.37-7.27 (m, 2H),7.29-7.22 (m, 2H), 7.06-6.93 (m, 4H), 6.88 (d, J=8.6 Hz, 1H), 5.82 (s,1H), 5.09 (s, 2H), 3.91 (q, J=6.9 Hz, 2H), 3.54 (bs, 2H), 3.36 (s, 3H),1.13 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 597.0 (M+H)⁺.

Example 46N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methoxyphenyl)acetamide

Example 46 was prepared according to the procedure used for thepreparation of Example 1H, substituting -2-(2-methoxyphenyl)acetic acidfor 2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.59-7.50 (m, 3H), 7.37-7.15 (m, 3H), 7.06-6.85 (m, 5H),5.82 (s, 1H), 3.92 (q, J=7.0 Hz, 2H), 3.62 (s, 2H), 3.36 (s, 3H), 1.14(t, J=6.9 Hz, 3H). MS (APCI+) m/z 521.0 (M+H)⁺.

Example 47N-(2-{[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}-2-oxoethyl)benzamide

Example 47 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-benzamidoacetic acid for2-(2-chloro-5-fluorophenyl)acetic acid.

¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.92-7.86 (m, 2H), 7.63-7.47 (m, 6H),7.37-7.27 (m, 1H), 7.07-6.94 (m, 2H), 6.91 (d, J=8.4 Hz, 1H), 5.83 (s,1H), 4.06 (s, 2H), 3.92 (q, J=7.0 Hz, 2H), 3.37 (s, 3H), 1.14 (t, J=6.9Hz, 3H). MS (APCI+) m/z 534.0 (M+H)⁺.

Example 482-cyclohexyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 48 was prepared according to the procedure used for thepreparation of Example 1H, substituting 2-cyclohexylacetic acid for2-(2-chloro-5-fluorophenyl)acetic acid.

¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.59-7.49 (m, 3H), 7.32 (ddd, J=11.2,8.6, 2.7 Hz, 1H), 7.06-6.91 (m, 2H), 6.88 (d, J=8.7 Hz, 1H), 5.82 (s,1H), 3.92 (q, J=7.0 Hz, 2H), 3.37 (s, 3H), 2.18 (d, J=7.0 Hz, 2H),1.82-1.55 (m, 6H), 1.29-1.06 (m, 6H), 1.06-0.89 (m, 2H). MS (APCI+) m/z497.1 (M+H)⁺.

Example 492-[(1S,4R)-bicyclo[2.2.1]hept-2-yl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 49 was prepared according to the procedure used for thepreparation of Example 1H, substituting2-((1S,4R)-bicyclo[2.2.1]heptan-2-yl)acetic acid for2-(2-chloro-5-fluorophenyl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ9.99 (s, 1H), 7.60-7.49 (m, 3H), 7.32 (ddd, J=11.2, 8.6, 2.7 Hz, 1H),7.06-6.93 (m, 2H), 6.88 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92 (q, J=7.0Hz, 2H), 3.37 (s, 3H), 2.26 (dd, J=13.9, 8.0 Hz, 1H), 2.22-2.05 (m, 2H),2.00-1.95 (m, 1H), 1.93-1.84 (m, 1H), 1.54-1.31 (m, 4H), 1.32-1.03 (m,7H). MS (APCI+) m/z 509.1 (M+H)⁺.

Example 505-[5-{[2-(benzyloxy)-3-methoxybenzyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

Example 50 was prepared according to the procedure used for thepreparation of Example 9, substituting2-(benzyloxy)-3-methoxybenzaldehyde for 3-(1H-pyrazol-1-yl)propanal andeluting with a gradient of acetonitrile (A) and 0.1% ammonium acetate inwater (B) in place of acetonitrile (A) and 0.1% trifluoroacetic acid inwater (B). ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.45-7.39 (m, 3H), 7.39-7.27(m, 3H), 7.22 (ddd, J=11.3, 8.6, 2.9 Hz, 1H), 7.09-7.01 (m, 1H),7.02-6.96 (m, 1H), 6.96-6.88 (m, 2H), 6.83-6.71 (m, 2H), 6.48-6.41 (m,2H), 5.75 (s, 1H), 5.01 (s, 2H), 4.13 (bs, 2H), 3.85 (s, 4H), 3.88-3.80(m, 5H), 3.31 (s, 3H), 1.06 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 598.9(M+H)⁺.

Example 515-[5-{[4-(benzyloxy)benzyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

Example 51 was prepared according to the procedure used for thepreparation of Example 9, substituting 4-(benzyloxy)benzaldehyde for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.47-7.36 (m, 4H), 7.34 (d, J=7.0 Hz, 1H), 7.33-7.27 (m,2H), 7.27-7.18 (m, 1H), 7.01-6.88 (m, 2H), 6.84-6.74 (m, 1H), 6.59 (dd,J=8.7, 2.9 Hz, 1H), 6.52 (d, J=2.8 Hz, 1H), 5.75 (s, 1H), 5.08 (s, 1H),4.17 (bs, 1H), 3.85 (q, J=6.9 Hz, 1H), 3.32 (s, 2H), 1.10 (s, 1H), 1.07(d, J=6.9 Hz, 3H). MS (APCI+) m/z 568.9 (M+H)⁺.

Example 525-{5-[(4-tert-butylbenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

Example 52 was prepared according to the procedure used for thepreparation of Example 9, substituting 4-(tert-butyl)benzaldehyde for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.45 (s, 1H), 7.39-7.18 (m, 5H), 6.97-6.88 (m, 1H),6.85-6.75 (m, 2H), 6.60 (dd, J=8.7, 2.9 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H),5.75 (s, 1H), 4.20 (bs, 2H), 3.85 (q, J=7.0 Hz, 2H), 3.32 (s, 3H), 1.27(s, 9H), 1.08 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 519.1 (M+H)⁺.

Example 535-{5-[(2,6-difluorobenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

Example 53 was prepared according to the procedure used for thepreparation of Example 9, substituting 2,6-difluorobenzaldehyde for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.49-7.36 (m, 2H), 7.23 (ddd, J=11.3, 8.6, 2.9 Hz, 1H),7.11 (t, J=7.8 Hz, 2H), 6.98-6.88 (m, 1H), 6.86-6.77 (m, 2H), 6.69 (dd,J=8.7, 2.9 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 5.77 (s, 1H), 4.26 (bs, 2H),3.87 (q, J=7.0 Hz, 2H), 3.33 (s, 3H), 1.10 (t, J=6.9 Hz, 3H). MS (APCI+)m/z 499.0 (M+H)⁺.

Example 545-[2-(2,4-difluorophenoxy)-5-{[3-(4-methoxyphenoxy)benzyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

Example 54 was prepared according to the procedure used for thepreparation of Example 9, substituting 3-(4-methoxyphenoxy)benzaldehydefor 3-(1H-pyrazol-1-yl)propanal and eluting with a gradient ofacetonitrile (A) and 0.1% ammonium acetate in water (B) in place ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400MHz, DMSO-d₆/D₂O) δ 7.43 (s, 1H), 7.34-7.19 (m, 1H), 7.12-7.06 (m, 1H),6.97-6.90 (m, 4H), 6.85-6.73 (m, 2H), 6.56 (dd, J=8.7, 2.9 Hz, 1H), 6.50(d, J=2.8 Hz, 1H), 5.76 (s, 1H), 4.24 (bs, 1H), 3.85 (q, J=7.0 Hz, 1H),3.32 (s, 3H), 1.07 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 584.9 (M+H)⁺.

Example 555-[5-({[5-(2-chlorophenyl)furan-2-yl]methyl}amino)-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

Example 55 was prepared according to the procedure used for thepreparation of Example 9, substituting5-(2-chlorophenyl)furan-2-carbaldehyde for 3-(1H-pyrazol-1-yl)propanaland eluting with a gradient of acetonitrile (A) and 0.1% ammoniumacetate in water (B) in place of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B). ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.80(dd, J=7.8, 1.7 Hz, 1H), 7.54 (dd, J=7.9, 1.3 Hz, 1H), 7.47 (s, 1H),7.41 (td, J=7.6, 1.3 Hz, 1H), 7.32 (td, J=7.6, 1.7 Hz, 1H), 7.24 (ddd,J=11.3, 8.6, 2.9 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 6.97-6.88 (m, 1H),6.87-6.78 (m, 2H), 6.73 (dd, J=8.7, 2.9 Hz, 1H), 6.65 (d, J=2.8 Hz, 1H),6.50 (d, J=3.4 Hz, 1H), 5.76 (s, 1H), 4.34 (bs, 2H), 3.85 (q, J=7.0 Hz,2H), 3.32 (s, 3H), 1.08 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 562.9 (M+H)⁺.

Example 564-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile

Example 56 was prepared according to the procedure used for thepreparation of Example 9, substituting 4-formylbenzonitrile for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.82-7.76 (m, 1H), 7.61-7.54 (m, 1H), 7.45 (s, 1H), 7.23(ddd, J=11.4, 8.6, 2.9 Hz, 1H), 6.97-6.87 (m, 1H), 6.84-6.75 (m, 1H),6.56 (dd, J=8.7, 2.9 Hz, 1H), 6.50 (d, J=2.8 Hz, 1H), 5.75 (s, 1H), 4.37(bs, 1H), 3.84 (q, J=6.9 Hz, 1H), 3.32 (s, 2H), 1.06 (t, J=6.9 Hz, 3H).MS (APCI+) m/z 488.0 (M+H)⁺.

Example 572-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile

Example 57 was prepared according to the procedure used for thepreparation of Example 9, substituting 2-formylbenzonitrile for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.83 (d, J=7.7 Hz, 1H), 7.74-7.66 (m, 1H), 7.61 (d, J=7.8Hz, 1H), 7.52-7.45 (m, 1H), 7.28-7.19 (m, 1H), 6.97-6.89 (m, 1H),6.86-6.77 (m, 1H), 6.60 (dd, J=8.6, 2.9 Hz, 1H), 6.56 (d, J=2.9 Hz, 1H),5.76 (s, 1H), 4.43 (bs, 1H), 3.86 (q, J=7.0 Hz, 1H), 3.33 (s, 2H), 1.08(t, J=6.9 Hz, 3H). MS (APCI+) m/z 488.0 (M+H)⁺.

Example 585-{2-(2,4-difluorophenoxy)-5-[(quinolin-4-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

Example 58 was prepared according to the procedure used for thepreparation of Example 9, substituting quinoline-4-carbaldehyde for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 8.84 (d, J=4.4 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.07 (d,J=8.5 Hz, 1H), 7.85-7.77 (m, 1H), 7.72-7.64 (m, 1H), 7.54 (d, J=4.5 Hz,1H), 7.47 (s, 1H), 7.23 (ddd, J=11.4, 8.6, 2.9 Hz, 1H), 6.98-6.88 (m,1H), 6.86-6.77 (m, 1H), 6.63 (dd, J=8.7, 2.9 Hz, 1H), 6.59 (d, J=2.8 Hz,1H), 5.73 (s, 1H), 4.81 (bs, 1H), 3.83 (q, J=6.9 Hz, 1H), 3.31 (s, 2H),1.05 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 514.0 (M+H)⁺.

Example 595-[5-{[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one

Example 59 was prepared according to the procedure used for thepreparation of Example 9, substituting5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.60-7.44 (m, 4H), 7.29-7.19 (m, 1H), 6.99-6.90 (m, 1H),6.89-6.80 (m, 1H), 6.69 (dd, J=8.7, 2.8 Hz, 1H), 6.60 (d, J=2.8 Hz, 1H),5.77 (s, 2H), 4.06 (bs, 1H), 3.87 (q, J=6.9 Hz, 2H), 3.33 (s, 3H), 2.29(s, 3H), 1.10 (d, J=6.9 Hz, 3H). MS (APCI+) m/z 577.0 (M+H)⁺.

Example 605-{2-(2,4-difluorophenoxy)-5-[({5-[2-(trifluoromethyl)phenyl]furan-2-yl}methyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

Example 60 was prepared according to the procedure used for thepreparation of Example 9, substituting5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.86-7.75 (m, 1H), 7.76-7.68 (m, 1H), 7.61-7.53 (m, 1H),7.46 (s, 1H), 7.28-7.19 (m, 1H), 6.97-6.88 (m, 1H), 6.87-6.79 (m, 1H),6.77-6.68 (m, 1H), 6.62 (d, J=2.8 Hz, 1H), 6.48 (d, J=3.4 Hz, 1H), 5.76(s, 1H), 4.32 (bs, 1H), 3.85 (q, J=7.0 Hz, 1H), 3.32 (s, 2H), 1.10 (s,1H), 1.07 (d, J=6.9 Hz, 2H). MS (APCI+) m/z 597.0 (M+H)+.

Example 615-{5-[(4-butoxybenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

Example 61 was prepared according to the procedure used for thepreparation of Example 9, substituting 4-butoxybenzaldehyde for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.45 (s, 1H), 7.32-7.14 (m, 3H), 6.91 (dd, J=20.3, 8.8Hz, 3H), 6.84-6.70 (m, 2H), 6.59 (dd, J=8.8, 2.8 Hz, 1H), 6.52 (d, J=2.9Hz, 1H), 5.75 (s, 1H), 4.17 (s, 2H), 3.94 (t, J=6.4 Hz, 2H), 3.85 (q,J=7.0 Hz, 2H), 3.32 (s, 3H), 1.74-1.57 (m, 2H), 1.51-1.32 (m, 2H), 1.08(t, J=7.0 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H). MS (APCI+) m/z 535.1 (M+H)⁺.

Example 625-{2-(2,4-difluorophenoxy)-5-[(4-phenoxybenzyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

Example 62 was prepared according to the procedure used for thepreparation of Example 9, substituting 4-phenoxybenzaldehyde for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.48-7.35 (m, 5H), 7.28-7.18 (m, 1H), 7.14 (t, J=7.4 Hz,1H), 7.02-6.88 (m, 5H), 6.85-6.76 (m, 2H), 6.61 (dd, J=8.7, 2.8 Hz, 1H),6.54 (d, J=2.8 Hz, 1H), 5.76 (s, 1H), 4.24 (bs, 2H), 3.86 (q, J=6.9 Hz,2H), 3.33 (s, 3H), 1.09 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 555.0 (M+H)⁺.

Example 633-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile

Example 63 was prepared according to the procedure used for thepreparation of Example 9, substituting 3-formylbenzonitrile for3-(1H-pyrazol-1-yl)propanal and eluting with a gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) in place of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.79 (s, 1H), 7.76-7.68 (m, 1H), 7.56 (t, J=7.7 Hz, 1H),7.45 (s, 1H), 7.23 (ddd, J=11.3, 8.6, 2.8 Hz, 1H), 6.97-6.88 (m, 1H),6.85-6.75 (m, 1H), 6.58 (dd, J=8.7, 2.9 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H),5.75 (s, 1H), 4.33 (bs, 1H), 3.85 (q, J=6.9 Hz, 1H), 3.33 (s, 2H), 1.07(t, J=6.9 Hz, 3H). MS (APCI+) m/z 488.0 (M+H)⁺.

Example 645-{2-(2,4-difluorophenoxy)-5-[(4-fluorobenzyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

A flask with stirbar and condenser was charged with Example 1G (0.255 g,0.685 mmol), 4-fluorobenzaldehyde (150 μL, 1.398 mmol) and acetic acid(0.40 mL, 6.99 mmol) in dichloromethane (7 mL). The solution was heatedto 60° C. for 1 hour, and then cooled in an ice bath. Sodiumtriacetoxyhydroborate (0.293 g, 1.382 mmol) was added in three portionsover 30 minutes, and the mixture was allowed to warm to ambienttemperature overnight. The reaction mixture was partitioned betweendichloromethane and aqueous sodium carbonate and the organics dried overanhydrous sodium sulfate. After filtration and solvent removal, theresidues were chromatographed on 12 g silica cartridge eluting with0-100% ethyl acetateheptane to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 7.49 (s, 1H), 7.42 (m, 2H), 7.24 (m, 1H), 7.17 (m, 2H),6.91 (m, 1H), 6.88 (m, 2H), 6.54 (m, 2H), 6.21 (t, J=6.0 Hz, 1H), 5.71(s, 1H), 4.24 (d, J=5.9 Hz, 2H), 3.84 (q, J=7.0 Hz, 2H), 2.49 (s, 3H),1.06 (t, J=7.0 Hz, 3H). MS (ESI) 481.2 (M+H)⁺.

Example 655-{5-[(cyclopropylmethyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one

Example 65 was prepared according to the procedure used for thepreparation of Example 64, substituting cyclopropanecarbaldehyde for4-fluorobenzaldehyde. ¹H NMR (300 MHz, DMSO-d₆) δ 7.49 (s, 1H), 7.23 (m,1H), 6.93 (m, 1H), 6.79 (m, 2H), 6.60-6.42 (m, 3H), 5.72 (s, 1H), 5.62(t, J=5.7 Hz, 1H), 3.85 (q, J=7.0 Hz, 2H), 2.88 (t, J=6.1 Hz, 2H), 2.26(s, 3H), 1.02 (t, J=7.0 Hz, 3H), 0.83 (m, 1H), 0.45 (m, 2H), 0.18 (m,2H). MS (ESI) 427.2 (M+H)⁺.

Example 661-(2-chloro-5-fluorophenyl)-N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]methanesulfonamide

A vial with stirbar was charged with Example 65 (0.0426 g, 0.100 mmol),2-chloro-5-fluorophenyl)methanesulfonyl chloride (0.048 g, 0.197 mmol)and triethylamine (50 μL, 0.359 mmol) in dichloromethane (1.0 mL). Themixture was stirred for 40 hours at ambient temperature. The reactionmixture was diluted with 30 mL of dichloromethane, washed with aqueousammonium chloride, dried over sodium sulfate, filtered, concentrated,and then purified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA),0-100%) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.62(s, 1H), 7.55 (dd, J=8.9, 5.2 Hz, 1H), 7.48-7.22 (m, 5H), 7.16-7.07 (m,2H), 7.11 (d, J=6.2 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 5.68 (s, 1H), 4.68(s, 2H), 3.95 (q, J=7.0 Hz, 2H), 3.56 (d, J=7 Hz, 2H), 3.38 (s, 3H),1.15 (t, J=6.9 Hz, 3H), 0.89 (m, 1H), 0.41 (m, 2H), 0.09 (m, 2H). MS(ESI) 633.1 (M+H)⁺.

Example 672-(2-chloro-5-fluorophenyl)-N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

A flask with stirbar was charged with Example 65 (0.079 g, 0.185 mmol),2-(2-chloro-5-fluorophenyl)acetyl chloride (0.094 g, 0.454 mmol) andtriethylamine (100 μL, 0.717 mmol) in dichloromethane (1.0 mL). Themixture was stirred overnight at ambient temperature, diluted with 30 mLof dichloromethane, washed with aqueous sodium bicarbonate, dried overanhydrous sodium sulfate, filtered, concentrated, and then purified byreverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%) to afford thetitle compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.62 (s, 1H), 7.46-7.27 (m,5H), 7.25-6.92 (m, 4H), 5.82 (s, 1H), 3.92 (q, J=7.0 Hz, 2H), 3.54 (s,2H), 3.52 (d, J=9.0 Hz, 2H), 3.37 (s, 3H), 1.11 (t, J=7.0 Hz, 3H), 0.88(m, 1H), 0.41 (m, 2H), 0.08 (m, 2H). MS (ESI) 597.2 (M+H)⁺.

Example 68N-[4-(benzyloxy)benzyl]-2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 68 was prepared according to the procedure used for thepreparation of Example 67, substituting Example 51 for Example 65. ¹HNMR (300 MHz, DMSO-d₆) δ 7.52 (s, 1H), 7.50-7.00 (m, 15H), 6.97-6.83 (m,3H), 5.80 (s, 1H), 5.06 (s, 2H), 4.80 (bds, 2H), 3.90 (q, J=7.0 Hz, 2H),3.54 (s, 2H), 3.35 (s, 3H), 1.09 (t, J=6.9 Hz, 3H). MS (ESI) 739.2(M+H)⁺.

Example 692-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(4-fluorobenzyl)acetamide

Example 69 was prepared according to the procedure used for thepreparation of Example 67, substituting Example 64 for Example 65. ¹HNMR (300 MHz, DMSO-d₆) δ 7.54 (s, 1H), 7.49-7.33 (m, 2H), 7.34-7.01 (m,10H), 6.88 (d, J=8.6 Hz, 1H), 5.80 (s, 1H), 4.86 (bds, 2H), 3.90 (d,J=7.0 Hz, 2H), 3.36 (s, 3H), 1.08 (t, J=6.9 Hz, 3H). MS (ESI) 651.2(M+H)⁺.

Example 702-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]propanamide

A 4 mL vial with stirbar was charged with sodium hydride, dry 95% (2.9mg, 0.115 mmol), placed in an ice bath and charged with a solution ofExample 1H (0.0527 g, 0.097 mmol) in DMF (1 mL). After stirring 10 minat 0° C., iodomethane (8 μL, 0.128 mmol) was added by syringe. After 1hour, the mixture was partitioned between 25 mL each of ethyl acetateand aqueous ammonium chloride. The organics were dried over anhydroussodium sulfate. After filtration and solvent removal, the material waspurified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%) toafford the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s, 1H),7.60 (d, J=2.6 Hz, 1H), 7.58 (s, 1H), 7.54-7.49 (m, 2H), 7.46-7.25 (m,2H), 7.22-6.92 (m, 3H), 6.87 (d, J=8.8 Hz, 1H), 5.79 (s, 1H), 4.15 (q,J=7.1 Hz, 1H), 3.93 (d, J=7.0 Hz, 2H), 3.34 (s, 3H), 1.47 (d, J=7.1 Hz,3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI) 557.1 (M+H)⁺.

Example 712-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-methylacetamide

A 4 mL vial with stir bar was charged with Example 1H (0.0626 g, 0.115mmol), powdered sodium hydroxide (25.1 mg, 0.628 mmol),tetrabutylammonium bromide (16.3 mg, 0.051 mmol), iodomethane (100 μL,1.599 mmol) and dichloromethane (1 mL). The mixture was stirred atambient temperature for 2 hours. The mixture was partitioned between 30mL each of dichloromethane and 1 M HCl. The organics were dried oversodium sulfate. After filtration and solvent removal, the residues werepurified by HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%) to afford thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 7.64 (s, 1H), 7.47-7.33 (m,4H), 7.26-7.03 (m, 4H), 6.94 (d, J=8.8 Hz, 1H), 5.83 (s, 1H), 3.94 (d,J=7.0 Hz, 2H), 5.59 (s, 2H), 3.38 (s, 3H), 3.20 (s, 3H), 1.47 (d, J =7.1Hz, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (ESI) 557.1 (M+H⁺).

Example 72N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamideExample 72AN-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide

A flask with stir bar was charged with Example 1G (1.028 g, 2.76 mmol),ethanesulfonyl chloride (0.55 mL, 5.80 mmol) and triethylamine (2.0 mL,14.35 mmol) in dichloromethane (28 ml). The solution was stirred atambient temperature for 18 hours. The mixture was stripped down byrotory evaporator, suspended in THF (18 mL), then treated with 1 Msodium hydroxide (9 mL, 9.00 mmol). The mixture was stirred at 60° C.for 20 hours. The mixture was cooled and shaken in a seperatory funnelwith 100 mL each of ethyl acetate and brine. The organics were driedover magnesium sulfate. After filtration and solvent removal the crudeproduct was chromatographed on a 40g silica cartridge eluting with 0-10%methanoldichloromethane to provide the title compound (1.13g, 88%).

Example 72BN-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide

To a solution of Example 72A (50 mg, 0.108 mmol) in DMF (1 mL) was addedNaH (7.7 mg, 0.32 mmol) and the mixture was stirred at room temperaturefor 30 minutes. Then (bromomethyl)cyclopropane (43.6 mg, 0.323 mmol) wasadded and the mixture was stirred at 50° C. for 18 hours. Water (10 mL)was added and the mixture extracted with ethyl acetate (3×15 mL). Thecombined organics were washed with brine, dried (MgSO₄), filtered, andconcentrated. The residue was purified by HPLC (C18, CH₃CN/water (0.1%NH₄HCO₃), 40-60%) to provide the title compound (5 mg, 8.96% yield). ¹HNMR (400 MHz, CD₃OD) δ 7.46 (s, 1H), 7.28 (dd, J=6.9, 2.6 Hz, 2H), 6.92(dd, J=12.2, 8.4 Hz, 2H), 6.80 (d, J=9.6 Hz, 2H), 5.81 (s, 1H), 3.87 (q,J=7.0 Hz, 2H), 3.43 (d, J=7.1 Hz, 2H), 3.38 (s, 3H), 3.00 (q, J=7.4 Hz,2H), 1.22 (t, J=7.4 Hz, 3H), 1.14 (t, J=7.0 Hz, 3H), 0.81 (d, J=7.8 Hz,1H), 0.33 (dd, J=8.0, 1.2 Hz, 2H), 0.01 (d, J=5.9 Hz, 2H). MS (ESI+) m/z519.2 (M+H)⁺.

Example 73N-benzyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide

Example 73 was prepared according to the procedure used for thepreparation of Example 72B, substituting benzyl bromide for(bromomethyl)cyclopropane. ¹H NMR (400 MHz, CD₃CN) δ 7.33-7.23 (m, 6H),7.22-7.15 (m, 2H), 7.07-6.86 (m, 3H), 6.74 (d, J=8.7 Hz, 1H), 5.74 (s,1H), 4.85 (s, 2H), 3.93 (q, J=7.0 Hz, 2H), 3.35 (s, 3H), 3.16 (q, J=7.4Hz, 2H), 1.35 (t, J=7.4 Hz, 3H), 1.18 (t, J=7.0 Hz, 3H). MS (ESI+) m/z555.2 (M+H)⁺.

Example 74N-(2-chlorobenzyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide

Example 74 was prepared according to the procedure used for thepreparation of Example 72B, substituting 2-chlorobenzyl bromide for(bromomethyl)cyclopropane. ¹H NMR (400 MHz, CD₃OD) δ 7.54-7.48 (m, 1H),7.44 (s, 1H), 7.31 (dd, J=6.3, 4.1 Hz, 3H), 7.29-7.21 (m, 2H), 7.08-6.78(m, 4H), 5.91 (s, 1H), 5.04 (s, 2H), 3.97 (q, J=7.0 Hz, 2H), 3.49 (s,3H), 3.24 (q, J=7.4 Hz, 2H), 1.40 (t, J=7.4 Hz, 3H), 1.23 (t, J=7.0 Hz,3H). MS (ESI+) m/z 589.2 (M+H)⁺.

Example 75N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(2-phenylethyl)ethanesulfonamide

To a 10 mL microwave tube were added Example 72A (100 mg, 0.215 mmol),K₂CO₃ (29.8 mg, 0.215 mmol), (2-bromoethyl)benzene (120 mg, 0.646 mmol)and DMF (1 mL). The mixture was heated at 170° C. for 15 minutes undermicrowave irradiation. The solid was filtered and the residue waspurified by HPLC (C18, CH₃CN/water (0.1% NH₄HCO₃), 40-70%) to give thetitle compound (102 mg, 0.179 mmol, 83% yield). ¹H NMR (400 MHz, CD₃OD)δ 7.55 (s, 1H), 7.35-7.28 (m, 2H), 7.24 (d, J=7.4 Hz, 2H), 7.21-7.11 (m,3H), 7.03 (d, J=5.5 Hz, 2H), 6.90 (d, J=8.5 Hz, 2H), 5.94 (s, 1H),4.05-3.91 (m, 4H), 3.51 (s, 3H), 3.05 (d, J=7.4 Hz, 2H), 2.82 (t, J=7.4Hz, 2H), 1.32-1.23 (m, 6H). MS (ESI+) m/z 569.2 (M+H)⁺.

Example 76N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamideExample 76AN-(4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)-1-phenylmethanesulfonamide

Example 76A was prepared according to the procedure used for thepreparation of Example 72A, substituting phenylmethanesulfonyl chloridefor ethanesulfonyl chloride.

Example 76BN-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide

Example 76B was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and(bromomethyl)cyclopropane for (2-bromoethyl)benzene, respectively. ¹HNMR (400 MHz, CD₃OD) δ 7.46 (s, 1H), 7.37 (d, J=6.3 Hz, 2H), 7.32-7.16(m, 4H), 7.03-6.82 (m, 5H), 5.87 (s, 1H), 4.37 (s, 2H), 3.93 (d, J=7.0Hz, 2H), 3.45 (s, 3H), 3.35 (d, J=7.1 Hz, 2H), 1.19 (t, J=7.0 Hz, 3H),0.82 (s, 1H), 0.35 (q, J=5.9 Hz, 2H), 0.01 (q, J=4.7 Hz, 2H). MS (ESI+)m/z 581.0 (M+H)⁺.

Example 77N-benzyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide

Example 77 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A andbenzyl bromide for (2-bromoethyl)benzene, respectively. ¹H NMR (400 MHz,CD₃OD) δ 7.46 (d, J=6.3 Hz, 2H), 7.41-7.33 (m, 4H), 7.29-7.19 (m, 5H),7.12 (dd, J=8.8, 2.7 Hz, 1H), 7.08-6.99 (m, 2H), 6.98-6.84 (m, 2H), 6.74(d, J=8.7 Hz, 1H), 5.91 (s, 1H), 4.73 (s, 2H), 4.52 (s, 2H), 3.97 (q,

J=7.0 Hz, 2H), 3.50 (s, 3H), 1.24 (t, J=7.0 Hz, 3H)., MS (ESI+) m/z617.2 (M+H)⁺.

Example 78N-(2-chlorobenzyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide

Example 78 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and2-chlorobenzyl bromide for (2-bromoethyl)benzene, respectively. ¹H NMR(400 MHz, CD₃OD) δ 7.53-7.46 (m, 3H), 7.45-7.36 (m, 4H), 7.33 (dd,J=7.2, 2.0 Hz, 1H), 7.30-7.18 (m, 3H), 7.14 (d, J=2.6 Hz, 1H), 7.11-7.02(m, 1H), 6.97-6.88 (m, 2H), 6.80 (d, J=8.8 Hz, 1H), 5.94 (s, 1H), 4.92(s, 2H), 4.56 (s, 2H), 3.99 (q, J=7.0 Hz, 2H), 3.52 (s, 3H), 1.26 (t,J=7.0 Hz, 3H). MS (ESI+) m/z 651.2 (M+H)⁺.

Example 79N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(2-phenylethyl)methanesulfonamide

Example 79 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A. ¹HNMR (400 MHz, CD₃OD) δ 7.51 (s, 1H), 7.41-7.28 (m, 5H), 7.26-7.18 (m,4H), 7.13-6.98 (m, 5H), 6.93 (t, J=8.6 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H),5.95 (s, 1H), 4.37 (s, 2H), 4.01 (d, J=7.0 Hz, 2H), 3.88-3.77 (m, 2H),3.52 (s, 3H), 2.80-2.68 (m, 2H), 1.27 (t, J=7.0 Hz, 3H). MS (ESI+) m/z631.2 (M+H)⁺.

Example 80N-[2-(2-chlorophenyl)ethyl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide

Example 80 was prepared according to the procedure used for thepreparation of Example 75, substituting 2-(2-bromoethyl)chlorobenzenefor (2-bromoethyl)benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.57 (s,1H),7.41-7.27 (m, 4H), 7.27-7.16 (m,2H), 7.14-6.99 (m, 2H), 6.93 (t,J=6.6Hz, 2H), 5.97 (s, 1H), 4.06-3.97 (m, 4H), 3.54 (s, 3H), 3.12 (q,J=7.4Hz, 2H), 3.04-2.96 (m, 2H), 1.36-1.25 (m, 6H). MS (ESI+) m/z 603.1(M+H)⁺.

Example 81N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3-phenyl-1H-pyrazol-1-yl)acetamide

A vial with stir bar was charged with 2-(3-phenyl-1H-pyrazol-1-yl)aceticacid (0.072 g, 0.356 mmol), Example 1G (0.109 g, 0.293 mmol), EDC (0.074g, 0.386 mmol) and HOBT (0.050 g, 0.327 mmol) in dichloromethane (4 mL).N-methylmorpholine (0.1 mL, 0.910 mmol) was added, and the mixture wasstirred at ambient temperature for 72 hours. The mixture was shaken in aseperatory funnel with 30 mL each of dichloromethane and aqueous sodiumcarbonate. The organics were dried over sodium sulfate, filtered andconcentrated. The crude material was purified by HPLC (C18, CH₃CN/water(0.1% TFA), 0-100%) to provide the trifluoroacetate salt of the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 7.80 (m, 3H),7.63-7.55 (m, 2H), 7.52 (dd, J=8.9, 2.6 Hz, 1H), 7.45-7.34 (m, 3H), 7.29(t, J=7.4 Hz, 1H), 7.01 (t, J=7.2 Hz, 2H), 6.90 (d, J=8.7 Hz, 1H), 6.75(d, J=2.2 Hz, 1H), 5.79 (s, 1H), 5.06 (s, 2H), 3.89 (dd, J=15.2, 8.1 Hz,2H), 3.34 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (ESI) m/z 557.1 (M+H⁺).

Example 822-(5-chloro-2-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide

Example 82 was prepared according to the procedure used for thepreparation of Example 81, substituting2-(5-chloro-2-fluorophenyl)acetic acid for2-(3-phenyl-1H-pyrazol-1-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆) δ10.29 (s, 1H), 7.61-7.56 (m, 2H), 7.54-7.46 (m, 2H), 7.43-7.32 (m, 2H),7.25 (t, J=9.1 Hz, 1H), 7.07-6.95 (m, 2H), 6.88 (d, J=8.8 Hz, 1H), 5.79(s, 1H), 3.91 (q, J=6.9 Hz, 2H), 3.34 (s, 3H), 1.13 (t, J=6.9 Hz, 3H).MS (ESI) m/z 543.1 (M+H⁺).

Example 83N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methyl-1,3-thiazol-4-yl)acetamide

The trifluoroacetate salt of Example 82 was prepared according to theprocedure used for the preparation of Example 81, substituting2-(2-methyl-1,3-thiazol-4-yl)acetic acid for2-(3-phenyl-1H-pyrazol-1-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆) δ10.23 (s, 1H), 7.60 (d, J=2.6 Hz, 2H), 7.53 (dd, J=8.8, 2.6 Hz, 1H),7.36 (ddd, J=11.2, 8.7, 2.7 Hz, 1H), 7.27 (s, 1H), 7.06-6.95 (m, 2H),6.88 (d, J=8.8 Hz, 1H), 5.79 (s, 1H), 3.91 (q, J=6.9 Hz, 2H), 3.74 (s,2H), 3.34 (s, 3H), 2.63 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (ESI) m/z512.1 (M+H⁺).

Example 84N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1H-pyrazol-1-yl)acetamide

A solution of Example 1G and DIPEA (0.15 M and 0.43 M in DMA,respectively, 257 μL, 0.04 mmol Example 1G (1.0 equivalent) and 0.12mmol DIPEA (3.0 equivalents)), HATU (0.2 M in DMA, 257 μL, 0.052 mmol,1.3 equivalents), and 2-(1H-pyrazol-1-yl)acetic acid (0.40 M in DMA, 121μL, 0.048 mmol, 1.2 equivalents) were aspirated from their respectivesource vials, mixed through a perfluoroalkoxy mixing tube (0 2 mm innerdiameter), and loaded into an injection loop. The reaction segment wasinjected into the flow reactor (Hastelloy coil, 0.75 mm inner diameter,1.8 mL internal volume) set at 100° C., and passed through the reactorat 180 μL min⁻¹ (10 minute residence time). Upon exiting the reactor,the reaction was loaded directly into an injection loop and purified bypreparative HPLC on a Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (50mm×21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium acetate inwater (B) was used, at a flow rate of 30 mL/min (0-0.5 min 5% A, 0.5-6.5min linear gradient 5-60% A, 6.5-7.0 min linear gradient 60-100% A,7.0-8.9 min 100% A, 8.9-9.0 min linear gradient 100-5% A, 9.0-10 min 5%A) to yield the title compound (7.33 mg, 39% yield). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.76 (d, J=2.3 Hz, 1H), 7.60-7.45 (m, 4H), 7.37-7.28 (m,1H), 7.07-6.87 (m, 3H), 6.31 (t, J=2.1 Hz, 1H), 5.82 (s, 1H), 5.00 (s,2H), 3.93 (q, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS(ESI) m/z 481.1 (M+H⁺).

Example 85N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(pyrimidin-5-yl)acetamide

Example 85 was prepared according to the procedure used for thepreparation of Example 84, substituting 2-(pyrimidin-5-yl)acetic acidfor 2-(1H-pyrazol-1-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 9.09(s, 1H), 8.76 (s, 2H), 7.58-7.49 (m, 3H), 7.32 (ddd, J=11.2, 8.6, 2.7Hz, 1H), 7.06-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92(q, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (ESI) m/z493.1 (M+H⁺).

Example 86N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3,5-dimethyl-1H-pyrazol-1-yl)acetamide

Example 86 was prepared according to the procedure used for thepreparation of Example 84, substituting2-(3,5-dimethyl-1H-pyrazol-1-yl)acetic acid for2-(1H-pyrazol-1-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.59-7.54 (m, 1H), 7.52 (dd, J=8.7, 2.7 Hz, 1H), 7.37-7.28 (m, 1H),7.07-6.94 (m, 2H), 6.91 (d, J=8.7 Hz, 1H), 5.86 (s, 1H), 5.82 (s, 1H),4.82 (s, 2H), 3.92 (q, J=6.9 Hz, 2H), 3.36 (s, 3H), 2.19 (s, 3H), 2.08(s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI) m/z 509.1 (M+H⁺).

Example 87N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1H-1,2,4-triazol-1-yl)acetamide

Example 87 was prepared according to the procedure used for thepreparation of Example 84, substituting 2-(1H-1,2,4-triazol-1-yl)aceticacid for 2-(1H-pyrazol-1-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ8.56 (s, 1H), 8.02 (s, 1H), 7.60-7.49 (m, 3H), 7.38-7.28 (m, 1H),7.08-6.95 (m, 2H), 6.91 (d, J=8.6 Hz, 1H), 5.83 (s, 1H), 5.13 (s, 2H),3.93 (q, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.14 (t, J=6.9 Hz, 3H). MS (ESI)m/z 482.1 (M+H⁺).

Example 88N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(pyrazin-2-yl)acetamide

Example 88 was prepared according to the procedure used for thepreparation of Example 84, substituting 2-(pyrazin-2-yl)acetic acid for2-(1H-pyrazol-1-yl)acetic acid. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 8.66 (m,1H), 8.59 (m, 1H), 8.54 (d, J=2.5 Hz, 1H), 7.59-7.49 (m, 3H), 7.37-7.27(m, 1H), 7.07-6.93 (m, 2H), 6.90 (d, J=8.7 Hz, 1H), 5.82 (s, 1H), 3.92(q, J=6.9 Hz, 2H), 3.36 (s, 3H), 1.13 (t, J=6.9 Hz, 3H). MS (ESI) m/z493.1 (M+H⁺).

Example 89N-[2-(2-chlorophenyl)ethyl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide

Example 89 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and2-(2-bromoethyl)chlorobenzene for (2-bromoethyl)benzene, respectively.1H NMR (400 MHz, CD₃OD) δ 7.52 (s, 1H), 7.43-7.41 (m, 2H), 7.37-7.30(m,4H), 7.25-7.18 (m, 4H), 7.12-7.00 (m, 3H), 6.97-6.91 (m, 1H),6.86 (d,J=8.7 Hz, 1H), 5.96 (s, 1H), 4.43 (s, 2H), 4.02 (q, J=7.0 Hz, 2H),3.92-3.81 (m, 2H), 3.54 (s, 3H), 2.99-2.88 (m, 2H), 1.28 (t, J=7.0 Hz,3H). MS (ESI+) m/z 665.2 (M+H⁺).

Example 90N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(1,3-thiazol-2-ylmethyl)methanesulfonamide

Example 90 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and2-(chloromethyl)-1,3-thiazole for (2-bromoethyl)benzene, respectively.¹H NMR (400 MHz, CD₃OD) δ 7.69 (d, J=3.3 Hz, 1H), 7.58 (d, J=3.3 Hz,1H), 7.51 (s, 1H), 7.50-7.45 (m, 1H), 7.42-7.35 (m, 1H), 7.29 (dd,J=8.8, 2.7 Hz, 1H), 7.20 (d, J=2.7 Hz, 1H), 7.13-6.98 (m, 1H), 6.96-6.89(m, 1H), 6.82 (d, J=8.8 Hz, 1H), 5.95 (s, 1H), 5.11 (s, 1H), 4.60 (s,1H), 4.01 (q, J=7.0 Hz, 1H), 3.53 (s, 1H), 1.27 (t, J=7.0 Hz, 1H). MS(ESI+) m/z 624.1(M+H)⁺.

Example 91N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyridin-3-ylmethyl)ethanesulfonamide

Example 91 was prepared according to the procedure used for thepreparation of Example 75, substituting 3-(bromomethyl)pyridine for(2-bromoethyl)benzene. ¹H NMR (400 MHz, CD₃OD) δ 8.48-8.33 (m, 2H), 7.83(d, J=7.9 Hz, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 7.41-7.35 (m, 1H),7.34-7.24 (m, 2H), 7.04 (s, 1H), 6.96 (d, J=5.5 Hz, 1H), 6.88 (d, J=1.3Hz, 1H), 6.81 (d, J=8.7 Hz, 1H), 5.91 (s, 1H), 4.95 (s, 2H), 3.96 (q,J=7.0 Hz, 2H), 3.49 (s, 3H), 3.23 (d, J=7.4 Hz, 2H), 1.40 (t, J=7.4 Hz,3H), 1.22 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 556.2 (M+H)⁺.

Example 92N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyridin-3-ylmethyl)methanesulfonamide

Example 92 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and3-(bromomethyl)pyridine for (2-bromoethyl)benzene, respectively. ¹H NMR(400 MHz, CD₃OD) δ 8.42 (dd, J=4.9, 1.5 Hz, 1H), 8.33 (d, J=1.6 Hz, 1H),7.77 (d, J=7.9 Hz, 1H), 7.55-7.47 (m, 2H), 7.46 (s, 1H), 7.43-7.34 (m,4H), 7.20-7.10 (m, 1H), 7.11-6.99 (m, 2H), 7.01-6.87 (m, 2H), 6.78 (d,J=8.7 Hz, 1H), 5.93 (d, J=5.9 Hz, 1H), 4.82 (s, 2H), 4.58 (s, 2H), 3.99(q, J=7.0 Hz, 2H), 3.52 (s, 3H), 1.25 (t, J=7.0 Hz, 3H). MS (ESI+) m/z618.2 (M+H)⁺.

Example 93N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyrimidin-5-ylmethyl)ethanesulfonamide

Example 93 was prepared according to the procedure used for thepreparation of Example 75, substituting 5-(bromomethyl)pyrimidine for(2-bromoethyl)benzene. ¹H NMR (400 MHz, CD₃OD) δ 9.07(s, 1H), 8.72 (s,2H), 7.55 (s, 1H), 7.43-7.29 (m, 2H), 7.13-6.82 (m, 4H), 5.95 (s, 1H),5.01 (s, 2H), 4.01(q, J=7.0 Hz, 2H), 3.52 (s, 3H), 3.31-3.24 (m, 2H),1.43 (t, J=7.4 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 557.2(M+H)⁺.

Example 94N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyrimidin-5-ylmethyl)methanesulfonamide

Example 94 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and5-(bromomethyl)pyrimidine for (2-bromoethyl)benzene, respectively. ¹HNMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 8.63 (s, 2H), 7.55-7.48 (m, 3H),7.44-7.36 (m, 3H), 7.18 (dd, J=8.8, 2.7 Hz, 1H), 7.14-7.06 (m, 2H),7.04-6.91 (m, 2H), 6.81 (d, J=8.7 Hz, 1H), 5.95 (s, 1H), 4.85 (s, 2H),4.61 (s, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.53 (s, 3H), 1.27 (t, J=7.0 Hz,3H). MS (ESI+) m/z 619.1 (M+H)⁺.

Example 95N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyrazin-2-ylmethyl)ethanesulfonamide

Example 95 was prepared according to the procedure used for thepreparation of Example 75, substituting 2-(chloromethyl)pyrazine for(2-bromoethyl)benzene. ¹H NMR (400 MHz, CD₃OD) δ 8.69 (d, J=1.3 Hz, 1H),8.59-8.55 (m, 1H), 8.51 (d, J=2.5 Hz, 1H), 7.54 (s, 1H), 7.44-7.36 (m,2H), 7.12-6.97 (m, 2H), 6.94-6.88 (m, 1H), 6.85 (d, J=8.7 Hz, 1H), 5.95(s, 1H), 5.12 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.52 (s, 3H), 3.31-3.26(m, 2H), 1.42 (t, J=7.4 Hz, 3H), 1.26 (t, J=7.0 Hz, 3H). MS (ESI+) m/z557.1 (M+H)⁺.

Example 96N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyrazin-2-ylmethyl)methanesulfonamide

Example 96 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and2-(chloromethyl)pyrazine for (2-bromoethyl)benzene, respectively. ¹H NMR(400 MHz, CD₃OD) δ 8.61 (d, J=1.3 Hz, 1H), 8.56-8.51 (m, 1H), 8.47 (d,J=2.6 Hz, 1H), 7.50-7.43 (m, 3H), 7.39-7.31(m, 3H), 7.24 (dd, J=8.8, 2.7Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 7.05 (s, 1H), 7.00-6.93(m, 1H), 6.89(d, J=1.3 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 5.92 (s, 1H), 4.97 (s, 2H),4.60(s, 2H), 3.98 (q, J=7.0 Hz, 2H), 3.50 (s, 3H), 1.23 (t, J=7.0 Hz,3H). MS (ESI+) m/z 619.2 (M+H)⁺.

Example 97N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-pyrazol-4-yl)methyl]ethanesulfonamide

Example 97 was prepared according to the procedure used for thepreparation of Example 75, substituting4-(chloromethyl)-1-methylpyrazole for (2-bromoethyl)benzene. ¹H NMR (400MHz, CD₃OD) δ 7.53 (s, 1H), 7.48 (s, 1H), 7.29-7.25 (m, 3H), 7.13-6.97(m, 2H), 6.97-6.83 (m, 2H), 5.94 (s, 1H), 4.77 (s, 2H), 4.01 (q, J=7.0Hz, 2H), 3.82 (s, 3H), 3.52 (s, 3H), 3.18 (q, J=7.4 Hz, 2H), 1.39 (t,J=7.4 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 559.2 (M+H)⁺.

Example 98N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-phenylmethanesulfonamide

Example 98 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and4-(chloromethyl)-1-methylpyrazole for (2-bromoethyl)benzene,respectively. ¹H NMR (400 MHz, CD₃OD) δ 7.49-7.43 (m, 3H), 7.41-7.33 (m,4H), 7.21(s, 1H), 7.12-6.97 (m, 4H), 6.92 (dd, J=2.7, 1.4 Hz, 1H), 6.80(d, J=8.7 Hz, 1H), 5.94 (s, 1H), 4.62 (s, 2H), 4.49 (s, 2H), 4.01 (q,J=7.0 Hz, 2H), 3.80 (s, 3H), 3.52 (s, 3H), 1.27 (t, J=7.0 Hz,3H). MS(ESI+) m/z 621.2 (M+H)⁺.

Example 99N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(1,3-thiazol-2-ylmethyl)ethanesulfonamide

Example 99 was prepared according to the procedure used for thepreparation of Example 75, substituting 2-(chloromethyl)thiazole for(2-bromoethyl)benzene. ¹H NMR (400 MHz, CD₃OD) δ 7.70 (d, J=3.3 Hz, 1H),7.59 (d, J=3.3 Hz, 1H), 7.56 (s, 1H), 7.47-7.39 (m, 2H), 7.14-6.98 (m,2H), 6.97-6.84 (m, 2H), 5.95 (s, 1H), 5.26 (s, 2H), 4.01 (q, J=7.0 Hz,2H), 3.53 (s, 3H), 3.28 (q, J=7.4 Hz, 2H), 1.41 (t, J=7.4 Hz, 3H), 1.27(t, J=7.0 Hz, 3H). MS (ESI+) m/z 562.2(M+H)⁺.

Example 100N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]ethanesulfonamide

Example 100 was prepared according to the procedure used for thepreparation of Example 75, substituting4-(chloromethyl)-1-methylimidazole for (2-bromoethyl)benzene.

1H NMR (400 MHz, CD₃OD) δ 7.53 (s, 1H), 7.48 (s, 1H), 7.34-7.25 (m, 2H),6.99 (d, J=5.5 Hz, 2H), 6.95 (s, 1H), 6.89 (t, J=9.4 Hz, 1H), 6.81 (d,J=8.7 Hz, 1H), 5.92 (s, 1H), 4.76 (s, 2H), 3.99 (q, J=7.0 Hz, 2H), 3.64(s, 3H), 3.50 (s, 3H), 3.16 (q, J=7.4 Hz, 2H), 1.35 (t, J=7.4 Hz, 3H),1.25 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 559.2(M+H)⁺.

Example 101N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]-1-phenylmethanesulfonamide

Example 101 was prepared according to the procedure used for thepreparation of Example 75, substituting Example 76A for Example 72A and4-(chloromethyl)-1-methylimidazole for (2-bromoethyl)benzene,respectively. ¹H NMR (400 MHz, CD₃OD) δ 7.50-7.46 (m, 2H), 7.44-7.39 (m,2H), 7.37-7.30 (m, 3H), 7.17-7.13 (m, 1H), 7.10-6.95 (m, 3H), 6.93-6.86(m, 2H), 6.75 (d, J=8.7 Hz, 1H), 5.92 (s, 1H), 4.67 (s, 2H), 4.47 (s,2H), 3.99 (q, J=7.0 Hz, 2H), 3.64 (s, 3H), 3.51 (s, 3H), 1.25 (t, J=7.0Hz, 3H). MS (ESI+) m/z 621.2 (M+H)⁺.

Example 102N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(2S)-1,4-dioxan-2-ylmethyl]ethanesulfonamide

A stock solution of Example 72A (0.16 M in DMF, 200 μL, 0.03 mmolExample 72A (1.0 equivalent)), K₂CO₃ (13.4 mg, 0.096 mmol, 3.2equivalents) and (25)-4-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate(0.04 M in DMA, 89 μL, 0.036 mmol, 1.2 equivalents), were aspirated fromtheir respective source vials, mixed through a perfluoroalkoxy mixingtube (0.2 mm inner diameter), and loaded into an injection loop. Thereaction segment was injected into the flow reactor (Hastelloy coil,0.75 mm inner diameter, 1.8 mL internal volume) set at 100° C., andpassed through the reactor at 180 μL min⁻¹ (10 minute residence time).Upon exiting the reactor, the reaction was loaded directly into aninjection loop and purified by preparative HPLC on a Phenomenex LunaC8(2) 5 μm 100 Å AXIA column (50 mm×21.2 mm). A gradient of acetonitrile(A) and 0.1% ammonium acetate in water (B) was used, at a flow rate of30 mL/min (0-0.5 min 5% A, 0.5-6 5 min linear gradient 5-60% A, 6.5-7.0min linear gradient 60-100% A, 7.0-8.9 min 100% A, 8.9-9.0 min lineargradient 100-5% A, 9.0-10 min 5% A) to yield the title compound (6.39mg, 32% yield). ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.56 (m, 1H), 7.44-7.38(m, 2H), 7.29 (m, 1H), 7.15-7.03 (m, 2H), 6.96 (m, 1H), 5.87 (s, 1H),4.02 (q, J=7.0 Hz, 2H), 3.80 (m, 1H),3.77-3.72 (m, 2H), 3.70-3.62 (m,2H), 3.61-3.49 (m, 4H), 3.44 (s, 3H), 3.20 (m, 2H), 1.31 (t, J=7.4 Hz,3H), 1.24 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 565.1 (M+H)⁺.

Example 103N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(tetrahydro-2H-pyran-4-ylmethyl)ethanesulfonamide

Example 103 was prepared according to the procedure used for thepreparation of Example 102, substituting4-(bromomethyl)tetrahydro-2H-pyran for (2S)-4-(1,4-dioxan-2-yl)methyl4-methylbenzenesulfonate. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.51 (s, 1H),7.38-7.32 (m, 2H), 7.27-7.19 (m, 1H), 7.04 (m, 2H), 6.91 (d, J=9.2 Hz,1H), 5.82 (s, 1H), 3.96 (q, J=7.0 Hz, 2H), 3.80 (d, J=11.7 Hz, 2H), 3.56(d, J=6.6 Hz, 2H), 3.38 (s, 3H), 3.26-3.16 (m, 3H), 3.10 (q, J=7.3 Hz,2H), 1.59 (m, 4H), 1.24 (t, J=9.0, 7.4 Hz, 3H), 1.18 (t, J=7.0 Hz, 3H).MS (ESI+) m/z 563.1 (M+H)⁺.

Example 104N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]ethanesulfonamide

Example 104 was prepared according to the procedure used for thepreparation of Example 102, substituting4-(2-bromoethyl)tetrahydro-2H-pyran for (2S)-4-(1,4-dioxan-2-yl)methyl4-methylbenzenesulfonate. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.64 (m, 1H),7.45-7.27 (m, 3H), 7.21-7.02 (m, 2H), 6.92-6.81 (m, 1H), 5.88 (s, 1H),3.96 (q, J=7.0 Hz, 2H), 3.83-3.74 (m, 2H), 3.69-3.64 (m, 2H), 3.40 (s,3H), 3.29-3.19 (m, 2H), 3.14 (q, J=7.4 Hz, 2H), 1.61-1.45 (m, 3H),1.39-1.27 (m, 2H), 1.27-1.21 (t, J=7.4 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H),1.13-1.05 (m, 2H). MS (ESI+) m/z 577.1 (M+H)⁺.

Biological Examples

(1) Bromodomain Domain Binding Assay

A time-resolved fluorescence resonance energy transfer (TR-FRET) assaywas used to determine the affinities of compounds of the Examples listedin Table 1 for each bromodomain of BRD4. His-tagged first (BD1: aminoacids K57-E168) and second (BD2: amino acids E352-E168) bromodomains ofBRD4 were expressed and purified. An Alexa647-labeled BET-inhibitor wasused as the fluorescent probe in the assay.

Synthesis of Alexa647-labeled bromodomain inhibitor compound2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid. Methyl2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate(see e.g., WO 2006129623)(100.95 mg, 0.243 mmol) was suspended in 1 mLmethanol to which was added a freshly prepared solution of lithiumhydroxide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken atambient temperature for 3 hours. The methanol was evaporated and the pHadjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) andextracted four times with ethyl acetate. The combined ethyl acetatelayers were dried over magnesium sulfate and evaporated to afford2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (85.3 mg, 87.0%); ESI-MS m/z=401.1 [(M+H)⁺] which was used directlyin the next reaction.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate).2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid)(85.3 mg, 0.213 mmol) was combined with2,2′-(ethane-1,2-diylbis(oxy))diethanamine (Sigma-Aldrich, 0.315 mg,2.13 mmol) were combined in 5 mL anhydrous dimethylformamide.(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphoniumhexafluorophosphate(V) (PyBOB, CSBio, Menlo Park Calif.; 332 mg, 0.638mmol) was added and the reaction shaken at ambient temperature for 16hours. The reaction was diluted to 6 mL with dimethylsulfoxide:water(9:1, v:v) and purified in two injections with time collection WatersDeltapak C18 200×25 mm column eluted with a gradient of 0.1%trifluoroacetic acid (v/v) in water and acetonitrile. The fractionscontaining the two purified products were lyophilized to affordN-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS m/z=531.1[(M+H)⁺]; 529.1 [(M−H)⁻].

N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide,2,2,2-trifluoroacetate.N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,24-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (5.4 mg, 0.0071 mmol) was combined withAlexa Fluor® 647 carboxylic acid, succinimidyl ester (Life Technologies,Grand Island, N.Y.; 3 mg, 0.0024 mmol) in 1 mL anhydrousdimethylsulfoxide containing diisopropylethylamine (1% v/v) and shakenat ambient temperature for 16 hours. The reaction was diluted to 3 mLwith dimethylsulfoxide:water (9:1, v:v) and purified in one injectionwith time collection Waters Deltapak C18 200×25 mm column eluted with agradient of 0.1% trifluoroacetic acid (v/v) in water and acetonitrile.The fractions containing the purified product were lyophilized to affordN-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,24-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide,2,2,2-trifluoroacetate (1.8 mg); MALDI-MS m/z=1371.1, 1373.1 [(M+H)⁺] asa dark blue powder.

Assay:

Compound dilution series were prepared in DMSO via an approximately3-fold serial dilution from one of the following:

-   Assay method A: 2.5 mM-797 nM-   Assay method B: 0.47 mM to 7.8 nM-   Assay method C: 0.047 mM to 0.78 nM or 5-fold serial dilution from    Assay method A

Compound dilutions were added directly into white, low-volume assayplates (Perkin Elmer Proxiplate 384 Plus# 6008280) using a Labcyte Echoin conjunction with Labcyte Access and Thermo Multidrop CombinLrobotics. Compounds were then suspended in eight microliters (μL) ofassay buffer (20 mM Sodium Phosphate, pH 6.0, 50 mM NaCl, 1 mMEthylenediaminetetraacetic acid disodium salt dihydrate, 0.01% TritonX-100, 1 mM DL-Dithiothreitol) containing His-tagged bromodomain,Europium-conjugated anti-His antibody (Invitrogen PV5596) andAlexa-647-conjugated probe.

The final concentration of 1X assay mixture for assay methods A, B and Ccontains 2% DMSO, 8 nM His-tagged bromodomain, 1 nM Europium-conjugatedanti-His-tag antibody and 100 nM or 30 nM probe (for BDI or BDII,respectively) and compound concentration in the range of: 49.02 μM-15.63nM for method A, 9.19 μM 150 pM for method B, and 0.92 μM 15 pM formethod C.

After a one-hour equilibration at room temperature, TR-FRET ratios weredetermined using an Envision multilabel plate reader (Ex 340, Em495/520).

TR-FRET data were normalized to the means of 24 no-compound controls(“high”) and 8 controls containing 1 μM un-labeled probe (“low”).Percent inhibition was plotted as a function of compound concentrationand the data were fit with the 4 parameter logistic equation to obtainIC₅₀s Inhibition constants (K_(i)) were calculated from the IC₅₀s, probeK_(d) and probe concentration. Typical Z′ values were between 0.65 and0.75. The minimum significant ratio was determined to evaluate assayreproducibility (Eastwood et al., (2006) J Biomol Screen, 11: 253-261).The MSR was determined to be 2.03 for BDI and 1.93 for BDII, and amoving MSR (last six run MSR overtime) for both BDI and BDII wastypically <3. The K_(u) values are reported in Table 1.

(2) MX-1 Cell Line Proliferation Assay

The impact of compounds of the Examples on cancer cell proliferation wasdetermined using the breast cancer cell line MX-1 (ATCC) in a 3-dayproliferation assay. MX-1 cells were maintained in RPMI supplementedwith 10% FBS at 37° C. and an atmosphere of 5% CO₂. For compoundtesting, MX-1 cells were plated in 96-well black bottom plates at adensity of 5000 cells/well in 90 μL of culture media and incubated at37° overnight to allow cell adhesion and spreading. Compound dilutionseries were prepared in DMSO via a 3-fold serial dilution from 3 mM to0.1 μM. The DMSO dilution series were then diluted 1:100 in phosphatebuffered saline, and 10 μL of the resulted solution were added to theappropriate wells of the MX-1 cell plate. The final compoundconcentrations in the wells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003,0.001, 0.0003, 0.0001, and 0.00003 μM. After the addition of compounds,the cells were incubated for 72 more hours and the amounts of viablecells were determined using the Cell Titer Glo assay kit (Promega)according to manufacturer suggested protocol.

Luminescence readings from the Cell Titer Glo assay were normalized tothe DMSO treated cells and analyzed using the GraphPad Prism softwarewith sigmoidal curve fitting to obtain EC₅₀s. The minimum significantratio (MSR) was determined to evaluate assay reproducibility (Eastwoodet al., (2006) J Biomol Screen, 11: 253-261). The overall MSR wasdetermined to be 2.1 and a moving MSR (last six run MSR overtime) hasbeen <2. The EC₅₀ values are reported in Table 1 for the indicatedcompounds.

TABLE 1 TR-FRET TR-FRET Binding Ki: Binding Ki: TR-FRET BRD4 BRD4Cellular Compounds of assay (BDI_K57- (BDII_E352- proliferation: Example# protocol E168) (μM) M457) (μM) EC₅₀ (μM) 1 B 0.331 0.0246 0.114 2 B0.271 0.0944 0.279 3 B 0.339 0.0777 0.433 4 B 0.244 0.0913 0.425 5 C0.212 0.0655 0.681 6 B 0.28 0.128 0.356 7 B 0.288 0.0809 0.187 8 B >2.380.0977 >3.0 9 A 0.991 0.0632 0.746 10 B 0.608 0.25 1.89 11 A 0.605 0.2750.884 12 B 0.32 0.292 1.02 13 B 0.375 0.135 1.48 14 B 0.248 0.0616 0.11115 B 0.255 0.683 ND 16 B 0.504 0.0282 >3.0 17 B 0.725 2.4 ND 18B >2.38 >4.08 ND 19 B 0.575 0.189 0.557 20 B 0.716 0.573 ND 21 B 1.281.91 ND 22 B 1.03 >4.08 ND 23 A 0.637 0.443 >3.0 24 A 0.731 0.304 0.83225 A 1.18 0.304 1.54 26 B 0.115 0.0714 ND 27 B 0.242 0.0365 0.73 28B >2.38 0.0541 0.605 29 B 0.131 0.0507 0.433 30 B 0.188 0.0389 >3.0 31 B0.14 0.0579 ND 32 B 0.248 0.185 ND 33 B 0.0718 0.0369 0.464 34 B 0.1560.108 ND 35 B 0.0843 0.00936 0.375 36 B 0.137 0.0662 0.476 37 B 1.690.0694 1.44 38 C 0.124 0.0748 0.779 39 B 0.329 0.0388 0.595 40 B 0.2840.0542 ND 41 B 0.0685 0.0108 0.398 42 B 0.911 0.0756 0.678 43 B 0.2240.11 ND 44 B 0.304 0.155 ND 45 B 2.32 0.112 0.981 46 B 0.0895 0.04770.449 47 B 0.226 0.0567 ND 48 B 0.111 0.0468 ND 49 B 0.116 0.0754 ND 50B 0.991 0.355 ND 51 B >2.38 0.176 ND 52 B >2.38 0.722 ND 53 B 0.3240.339 ND 54 B >2.38 1.81 ND 55 B >2.38 0.575 ND 56 B 0.247 0.0601 ND 57B 0.15 0.18 0.712 58 C 0.302 0.127 ND 59 B 0.767 0.193 ND 60 B >2.380.904 ND 61 B 2.19 0.489 ND 62 B >2.38 0.24 ND 63 B 0.352 0.293 ND 64C >0.238 0.0618 0.508 65 C 0.193 0.0967 ND 66 C 0.594 0.0384 >1.0 67C >0.238 0.128 >1.0 68 C >0.238 >0.408 ND 69 C >0.238 >0.408 ND 70 C0.224 0.0864 >1.0 71 C 0.182 0.0813 >1.0 72 C 0.0609 0.00228 0.233 73 C0.0941 0.00966 >1.0 74 C 0.191 0.0135 0.464 75 C 0.324 0.0478 0.614 76 C1.04 0.0131 >1.0 77 C >0.238 0.114 >1.0 78 C >0.238 0.0713 >1.0 79 C0.915 0.288 >1.0 80 C >0.238 0.0561 >1.0 81 C >0.238 0.0219 >1.0 82 C0.136 0.063 >1.0 83 C 0.139 0.0365 0.304 84 C >0.238 0.0675 ND 85 C0.171 0.131 ND 86 C >0.238 0.0226 ND 87 C >0.238 0.171 ND 88 C 0.1840.115 ND 89 C >0.238 0.202 ND 90 C >0.238 0.0444 >1.0 91 C 0.116 0.01760.505 92 C 0.554 0.0924 >1.0 93 C >0.238 0.0563 >1.0 94 C >0.238 0.266ND 95 C 0.194 0.0289 >1.0 96 C >0.238 0.085 >1.0 97 C 0.122 0.0173 0.5598 C >0.238 0.0794 >1.0 99 C 0.11 0.00458 0.555 100 C 0.358 0.0346 >1.0101 C >0.238 0.0928 >1.0 102 C 0.139 0.0237 0.71 103 C 0.233 0.01170.677 104 C 0.185 0.0239 ND ND = Not Determined

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations andor methods of useof the invention, may be made without departing from the spirit andscope thereof. All publications, patents, and patent applications citedherein are hereby incorporated by reference in their entirety for allpurposes.

The invention claimed is:
 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof

wherein R¹ is C₁-C₃ alkyl or C₁-C₃ haloalkyl; R² is H; R³ is —O—C₁-C₆ alkyl, —OCD₂CH₃, or —OCD₂CD₃; Y¹ is N or CR⁴, wherein R⁴ is H, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; A² is CR⁵, and A¹, A³, and A⁴ are CR⁶; or A² is CR⁵, A¹ and A³ are CR⁶, and A⁴ is N; R⁵ is —N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), —N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b), —N(R^(5d))SO₂—C₁-C₆ alkylellyl-R^(5c), —N(R^(5d))C(O)N(R^(5d))-G¹, —N(R^(5d))C(O)N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), —N(R^(5d))SO₂N(R^(5d))—C₁-C₆ alkylenyl-R⁵a, —C(O)N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), or —SO₂N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), wherein R^(5a), at each occurrence, is independently G¹, —OR^(5aa), —OC(O)R^(5dd), —SR^(5aa), —S(O)R^(5aa), —SO₂R^(5aa), —SO₂NR^(5bb)R^(5cc), —NR^(5bb)R^(5cc), —NR^(5bb)C(O)R^(5dd), —NR^(5bb)SO₂R^(5dd), —NR^(5bb)C(O)OR^(5dd), —NR^(5bb)C(O)NR^(5bb)R^(5cc), —NR^(5bb)SO₂NR^(5bb)R^(5cc), —C(O)R^(5aa), —C(O)OR^(5aa), or —C(O)NR^(5bb)R^(5cc), R^(5b) is G¹, —OR^(5aa), —OC(O)R^(5dd), —SR^(5aa), —S(O)R^(5aa), —SO₂R^(5aa), —SO₂NR^(5bb)R^(5cc), —N(R^(5bb))(G¹), —NR^(5bb)—(C₁-C₆ alkylenyl)-G¹, —NR^(5bb)C(O)R^(5dd), —NR^(5bb)SO₂R^(5dd), —NR^(5bb)C(O)OG¹, —NR^(5bb)C(O)O—(C₁-C₆ alkylenyl)-G¹, —NR^(5bb)C(O)NR^(5bb)R^(5cc), —NR^(5bb)SO₂NR^(5bb)R^(5cc), —C(O)R^(5aa), —C(O)OR^(5aa), or —C(O)NR^(5bb)R^(5cc), R^(5c) is —OR^(5aa), —OC(O)R^(5dd), —SR^(5aa), —S(O)R^(5aa) —SO₂R^(5aa), —SO₂NR^(5bb)R^(5cc), —NR^(5bb)R^(5cc), —NR^(5bb)C(O)R^(5dd), —NR^(5bb)SO₂R^(5dd), —NR^(5bb)C(O)OR^(5dd), —NR^(5bb)C(O)NR^(5bb)R^(5cc), —NR^(5bb)SO₂NR^(5bb)R^(5cc), —C(O)R^(5aa), —C(O)OG¹, —C(O)O—(C₁-C₆ alkylenyl)-G¹, or —C(O)NR^(5bb)R^(5cc), R^(5d), at each occurrence, is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, —OR^(5aa), —OC(O)R^(5dd), —SR^(5aa), —S(O)R^(5aa), —SO₂R^(5aa), —SO₂NR^(5bb)R^(5cc), —NR^(5bb)R^(5cc), —NR^(5bb)C(O)R^(5dd), —NR^(5bb)SO₂R^(5dd), —NR^(5bb)C(O)OR^(5dd), —NR^(5bb)C(O)NR^(5bb)R^(5cc), —NR^(5bb)SO₂NR^(5bb)R^(5cc), —C(O)R^(5aa), —C(O)OR^(5aa), —C(O)NR^(5bb)R^(5cc), —(C₁-C₆ alkylenyl)-G¹, —(C₁-C₆ alkylenyl)-OR^(5aa), —(C₁-C₆ alkylenyl)-OC(O)R^(5dd), —(C₁-C₆ alkylenyl)-SR^(5aa), —(C₁-C₆ alkylenyl)-S(O)R^(5aa), —(C₁-C₆ alkylenyl)-SO₂R^(5aa), —(C₁-C₆ alkylenyl)-SO₂NR^(5bb)R^(5cc), —(C₁-C₆ alkylenyl)—NR^(5bb)R^(5cc), —(C₁-C₆ alkylenyl)-NR^(5bb)C(O)R^(5dd), —(C₁-C₆ alkylenyl)-NR^(5bb)SO₂R^(5dd), —(C₁-C₆ alkylenyl)-NR^(5bb)C(O)OR^(5dd), —(C₁-C₆ alkylenyl)-NR^(5bb)C(O)NR^(5bb)R^(5cc), —(C₁-C₆ alkylenyl)-NR^(5bb)SO₂NR^(5bb)R^(5cc), —(C₁-C₆ alkylenyl)-C(O)R^(5aa), —(C₁-C₆ alkylenyl)-C(O)OR^(5aa), or —(C₁-C₆ alkylenyl)-C(O)NR^(5bb)R^(5cc); R⁶ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, or —CN; R^(5aa), R^(5bb), and R^(5cc), at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹; R^(5dd), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹; G¹, at each occurrence, is independently aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(1g) groups, Y² is -L-G²; wherein L is O or N(R^(x)) wherein R^(x) is H or C₁-C₆ alkyl; G² is aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(2g) groups; R^(1g) and R^(2g), at each occurrence, are each independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, —OR^(z1), —OC(O)R^(z2), —OC(O)NR^(z3)R^(z4), —SR^(z1), —S(O)₂R^(z1), —S(O)₂NR^(z3)R^(z4), —C(O)R^(z1), —C(O)OR^(z1), —C(O)NR^(z3)R^(z4), —NR^(z3)R^(z4), —N(R^(z3))C(O)R^(z2), —N(R^(z3))S(O)₂R^(z2), —N(R^(z3))C(O)O(R^(z2)), —N(R^(z3))C(O)NR^(z3)R^(z4), —N(R^(z3))S(O)₂NR^(z3)R^(z4), G³, —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆ alkylenyl)-OC(O)R^(z2), —(C₁-C₆ alkylenyl)-OC(O)NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-S(O)₂R^(z1), —(C₁-C₆ alkylenyl)-S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-C(O)R^(z1), —(C₁-C₆ alkylenyl)-C(O)OR^(z1), —(C₁-C₆ alkylenyl)-C(O)NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)—NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)—N(R^(z3))C(O)R^(z2), —(C₁-C₆ alkylenyl)-N(R^(z3))S(O)₂R^(z2), —(C₁-C₆ alkylenyl)-N(R^(z3))C(O)O(R^(z2)), —(C₁-C₆ alkylenyl)-N(R^(z3))C(O)NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-N(R^(z3))S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-CN, or —(C₁-C₆ alkylenyl)-G³; R^(z1), R^(z3), and R^(z4), at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G³, or —C₁-C₆ alkylenyl-G³; R^(z2), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G³, or —C₁-C₆ alkylenyl-G³; G³ is aryl, heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(3g) groups, R^(3g), at each occurrence, is independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, —OR^(a), —OC(O)R^(b), —OC(O)NR^(c)R^(d), —SR^(a), —S(O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(d), —NR^(c)R^(d), —N(R^(c))C(O)R^(b), —N(R^(c))S(O)₂R^(b), —N(R^(c))C(O)O(R^(b)), —N(R^(c))C(O)NR^(c)R^(d), —N(R^(c))S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-OC(O)R^(b), —(C₁-C₆ alkylenyl)-OC(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)—NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(c))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(c))S(O)₂R^(b), —(C₁-C₆ alkylenyl)-N(R^(c))C(O)O(R^(b)), —(C₁-C₆ alkylenyl)-N(R^(c))C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(c))S(O)₂NR^(c)R^(d), or —(C1-C6 alkylenyl)-CN; R^(a), R^(c), and R^(d), at each occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl, and R^(b), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl.
 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl.
 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R³ is —O—C₁-C₆ alkyl.
 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y¹ is CR⁴.
 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is O and G² is phenyl, C₃-C₆ cycloalkyl, or C₄-C₆ heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(2g) groups.
 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A² is CR⁵, and A¹, A³, and A⁴ are CR⁶.
 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R⁵ is N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b), N(R^(5d))SO₂—C₁-C₆ allcylenyl-R^(5c), or N(R^(5d))C(O)N(R^(5d))-G¹.
 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl; Y¹ is CR⁴; and R³ is —O—C₁-C₃ alkyl.
 9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein A² is CR⁵, and A¹, A³, and A⁴ are CR⁶.
 10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein L is O ; and G² is phenyl or C₃-C₆ cycloalkyl; each of which is optionally substituted with 1, 2, 3, 4, or 5 R^(2g) groups.
 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R⁵ is N(R^(5d))—C₁-C₆ alkylenyl-R^(5a), N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b), N(R^(5d))SO₂—C₁-C₆ alkylenyl-R^(5c), or N(R^(5d))C(O)N(R^(5d))-G¹.
 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R⁴ is H; and G² is phenyl which is optionally substituted with 1, 2, or 3 R^(2g) groups.
 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R⁵ is N(R^(5d))—C₁-C₆ alkylenyl-R^(5a).
 14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R^(5d) is H or SO₂R^(5aa); and R^(5a) is G¹.
 15. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R^(5d) is SO₂R^(5aa); R^(5aa) is C₁-C₃ alkyl or —(C₁-C₃ alkylenyl)-G¹; and R^(5a) is G¹; wherein G¹ is phenyl, naphthyl, C₃-C₆ cycloalkyl, heteroaryl, or heterocycle; each of which is optionally substituted.
 16. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R^(5d) is SO₂R^(5aa); R^(5aa) is —(C₁-C₃ alkylenyl)-G¹ wherein G¹ is optionally substituted phenyl; and R^(5a) is G¹; wherein G¹ is optionally substituted phenyl or optionally substituted cyclopropyl.
 17. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R⁵ is N(R^(5d))C(O)—C₁-C₆ alkylenyl-R^(5b).
 18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R^(5d) is H, C₁-C₃ alkyl, or —(C₁-C₆ alkylenyl)-G¹; R^(5b) is G¹, —OR^(5aa), —S(O)₂R^(5aa), —NR^(5bb)C(O)R^(5dd), —NR^(5bb)S(O)₂R^(5dd), —C(O)R^(5aa), or —C(O)NR^(5bb)R^(5cc); R^(5aa), R^(5cc), and R^(5dd) are each independently optionally substituted phenyl or optionally substituted benzyl; and R^(5bb) is H or C₁-C₃ alkyl.
 19. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R^(5d) is H; and R^(5b) is G¹ wherein G¹ is phenyl, naphthyl, C₃-C₆ cycloalkyl, heterocycle, or heteroaryl, each of which is optionally substituted.
 20. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R^(5d) is H; and R^(5b) is G¹ wherein G¹ is optionally substituted phenyl or optionally substituted C₅-C₆ heteroaryl.
 21. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R⁵ is N(R^(5d))C(O)N(R^(5d))-G¹.
 22. The compound of any one of claims 9-21, or a pharmaceutically acceptable salt thereof, wherein R⁶ is H.
 23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of 2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3,4-dihydro-2H-chromen-6-yl)acetamide; 2-(4-chloro-2-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(6-methylpyridin-3-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1,5-dimethyl-1H-pyrazol-3-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methyl-1,3-thiazol-5-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-[3-(2-fluorophenyl)-1H-pyrazol-1-yl]acetamide; 5-[2-(2,4-difluorophenoxy)-5-{[3-(1H-pyrazol-1-yl)propyl] amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 5-{2-(2,4-difluorophenoxy)-5-[(6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[2-(2,4-difluorophenoxy)-5-{[(6-methylpyridin-2-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[2-(2,4-difluorophenoxy)-5-{[(3-methylpyridin-2-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[2-(2,4-difluorophenoxy)-5-{[(1-methyl-1H-pyrazol-5-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; methyl 4-{[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}butanoate; 1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3-phenoxyphenyl)urea; 1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,4-dimethylphenyl)urea; 1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3,5-dimethylphenyl)urea; 1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-[4-(trifluoromethoxy)phenyl]urea; 1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,5-dimethylphenyl)urea; 1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(4-fluorophenyl)urea; 1-(3-chlorophenyl)-3-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]urea; 1-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(3-methoxyphenyl)urea; 5-{2-(2,4-difluorophenoxy)-5-[(1,3-oxazol-5-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[2-(2,4-difluorophenoxy)-5-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[2-(2,4-difluorophenoxy)-5-{[(1-ethyl-1H-pyrazol-3-yl)methyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-5-oxo-5-phenylpentanamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(phenylsulfonyl)propanamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3-phenoxyphenyl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-[4-(methylsulfonyl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-phenoxypropanamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(naphthalen-1-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-{[(4-methylphenyl)sulfonyl]amino}acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(4-methylphenoxy)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-(2,3,4-trimethoxyphenyl)propanamide; 2-(benzyloxy)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; 2-(1,2-benzoxazol-3-yl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(4-phenoxyphenyl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-phenylbutanamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(naphthalen-2-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N′-phenylpentanediamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-3-phenylpropanamide; 2-(biphenyl-4-yl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-oxo-4-phenylbutanamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-4-phenoxybutanamide; 2-[4-(benzyloxy)phenyl]-N-4-[2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methoxyphenyl)acetamide; N-(2-{[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}-2-oxoethyl)benzamide; 2-cyclohexyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; 2-[(1S,4R)-bicyclo[2.2.1]hept-2-yl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; 5-[5-{[2-(benzyloxy)-3-methoxybenzyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[5-{[4-(benzyloxy)benzyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 5-{5-[(4-tert-butylbenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 5-{5-[(2,6-difluorobenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[2-(2,4-difluorophenoxy)-5-{[3-(4-methoxyphenoxy)benzyl]amino}phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[5-({[5-(2-chlorophenyl)furan-2-yl]methyl}amino)-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 4-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile; 2-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile; 5-{2-(2,4-difluorophenoxy)-5-[(quinolin-4-ylmethyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 5-[5-{[(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)methyl]amino}-2-(2,4-difluorophenoxy)phenyl]-4-ethoxy-1-methylpyridin-2(1H)-one; 5-{2-(2,4-difluorophenoxy)-5-[({5-[2-(trifluoromethyl)phenyl]furan-2-yl}methyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 5-{5-[(4-butoxybenzyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 5-{2-(2,4-difluorophenoxy)-5-[(4-phenoxybenzyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 3-({[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]amino}methyl)benzonitrile; 5-{2-(2,4-difluorophenoxy)-5-[(4-fluorobenzyl)amino]phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 5-{5-[(cyclopropylmethyl)amino]-2-(2,4-difluorophenoxy)phenyl}-4-ethoxy-1-methylpyridin-2(1H)-one; 1-(2-chloro-5-fluorophenyl)-N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]methanesulfonamide; 2-(2-chloro-5-fluorophenyl)-N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; N-[4-(benzyloxy)benzyl]-2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; 2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(4-fluorobenzyl)acetamide; 2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]propanamide; 2-(2-chloro-5-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-methylacetamide; N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide; N-benzyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide; N-(2-chlorobenzyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(2-phenylethyl)ethanesulfonamide; N-(cyclopropylmethyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide; N-benzyl-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide; N-(2-chlorobenzyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(2-phenylethyl)methanesulfonamide; N-[2-(2-chlorophenyl)ethyl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3-phenyl-1H-pyrazol-1-yl)acetamide; 2-(5-chloro-2-fluorophenyl)-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(2-methyl-1,3-thiazol-4-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1H-pyrazol-1-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(pyrimidin-5-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(3,5-dimethyl-1H-pyrazol-1-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(1H-1,2,4-triazol-1-yl)acetamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-2-(pyrazin-2-yl)acetamide; N-[2-(2-chlorophenyl)ethyl]-N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenylmethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(1,3-thiazol-2-ylmethyl)methanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyridin-3-ylmethyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyridin-3-ylmethyl)methanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyrimidin-5-ylmethyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyrimidin-5-ylmethyl)methanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(pyrazin-2-ylmethyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-1-phenyl-N-(pyrazin-2-ylmethyl)methanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-pyrazol-4-yl)methyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1-phenylmethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(1,3-thiazol-2-ylmethyl)ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(1-methyl-1H-imidazol-4-yl)methyl]-1-phenylmethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[(2S)-1,4-dioxan-2-ylmethyl]ethanesulfonamide; N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-(tetrahydro-2H-pyran-4-ylmethyl)ethanesulfonamide; and N-[4-(2,4-difluorophenoxy)-3-(4-ethoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl]-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]ethanesulfonamide.
 24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. 